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Chilvery S, Yelne A, Khurana A, Saifi MA, Bansod S, Anchi P, Godugu C. Acetaminophen induced hepatotoxicity: An overview of the promising protective effects of natural products and herbal formulations. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 108:154510. [PMID: 36332383 DOI: 10.1016/j.phymed.2022.154510] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 08/06/2022] [Accepted: 10/16/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND The liver plays an important role in regulating the metabolic processes and is the most frequently targeted organ by toxic chemicals. Acetaminophen (APAP) is a well-known anti-allergic, anti-pyretic, non-steroidal anti-inflammatory drug (NSAID), which upon overdose leads to hepatotoxicity, the major adverse event of this over-the-counter drug. PURPOSE APAP overdose induced acute liver injury is the second most common cause that often requires liver transplantation worldwide, for which N-acetyl cysteine is the only synthetic drug clinically approved as an antidote. So, it was felt that there is a need for the novel therapeutic approach for the treatment of liver diseases with less adverse effects. This review provides detailed analysis of the different plant extracts; phytochemicals and herbal formulations for the amelioration of APAP-induced liver injury. METHOD The data was collected using different online resources including PubMed, ScienceDirect, Google Scholar, Springer, and Web of Science using keywords given below. RESULTS Over the past decades various reports have revealed that plant-based approaches may be a better treatment choice for the APAP-induced hepatotoxicity in pre-clinical experimental conditions. Moreover, herbal compounds provide several advantages over the synthetic drugs with fewer side effects, easy availability and less cost for the treatment of life-threatening diseases. CONCLUSION The current review summarizes the hepatoprotective effects and therapeutic mechanisms of various plant extracts, active phytoconstituents and herbal formulations with potential application against APAP induced hepatotoxicity as the numbers of hepatoprotective natural products are more without clinical relativity. Further, pre-clinical pharmacological research will contribute to the designing of natural products as medicines with encouraging prospects for clinical application.
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Affiliation(s)
- Shrilekha Chilvery
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India
| | - Amit Yelne
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India
| | - Amit Khurana
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India
| | - Mohd Aslam Saifi
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India
| | - Sapana Bansod
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India
| | - Pratibha Anchi
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India
| | - Chandraiah Godugu
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India.
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Wang YP, Wang YD, Liu YP, Cao JX, Yang ML, Wang YF, Khan A, Zhao TR, Cheng GG. 6'- O-Caffeoylarbutin from Que Zui tea ameliorates acetaminophen-induced liver injury via enhancing antioxidant ability and regulating the PI3K signaling pathway. Food Funct 2022; 13:5299-5316. [PMID: 35441652 DOI: 10.1039/d2fo00507g] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Que Zui tea (QT), a traditional herbal tea in China, has a significant hepatoprotective effect. 6'-O-Caffeoylarbutin (CA) is the most abundant chemical compound in the QT. However, the hepatoprotective effect of CA has not been investigated. This study is aimed to evaluate the protective effect of CA on acetaminophen (APAP) induced hepatotoxicity in vivo and in vitro and its possible underlying mechanism. In APAP-induced HepG-2 cells, CA inhibited intracellular ROS accumulation and cell apoptosis, and improved the expression of antioxidants including SOD, CAT and GSH. In APAP-administrated mice, CA pretreatment remarkably ameliorated the histopathological damage and inflammatory response, and antioxidant enzyme activity in the serum and liver tissues. Moreover, the immunohistochemistry and immunofluorescence assay results revealed that the CA markedly reduced ROS production and apoptosis, and activated antioxidant transcription factor Nrf2 in the liver. Meanwhile, molecular docking results showed that the strong binding force of CA and PI3K was due to the higher number of hydrogen- and π-bonds with active site residues. Notably, CA pretreatment significantly regulated the expression of PI3K, Akt, Nrf2, NQO1, HO-1, Bcl-2, Bax, caspase-3, and caspase-9 proteins in APAP-treated liver tissues. These data demonstrated that CA had a protective effect against APAP-induced hepatotoxicity via regulating the PI3K/Akt and Nrf2 signaling pathway.
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Affiliation(s)
- Yong-Peng Wang
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China.
| | - Yu-Dan Wang
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China. .,National and Local Joint Engineering Research Center for Green Preparation Technology of Biobased Materials, Yunnan Minzu University, Kunming, 650500, China
| | - Ya-Ping Liu
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China.
| | - Jian-Xin Cao
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China.
| | - Mei-Lian Yang
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China.
| | - Yi-Fen Wang
- Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
| | - Afsar Khan
- Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan
| | - Tian-Rui Zhao
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China.
| | - Gui-Guang Cheng
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China.
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He Y, Xu X, Qiu J, Yin W, Sima Y, Xu S. Bombyx mori used as a fast detection model of liver melanization after a clinical drug – Acetaminophen exposure. JOURNAL OF ASIA-PACIFIC ENTOMOLOGY 2020; 23:177-185. [DOI: 10.1016/j.aspen.2019.11.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Auriculatone Sulfate Effectively Protects Mice Against Acetaminophen-Induced Liver Injury. Molecules 2019; 24:molecules24203642. [PMID: 31600996 PMCID: PMC6832223 DOI: 10.3390/molecules24203642] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 09/26/2019] [Accepted: 09/30/2019] [Indexed: 01/28/2023] Open
Abstract
Acetaminophen (APAP) overdose is very common worldwide and has been widely recognized as the leading cause of drug-induced liver injury in the Western world. In our previous investigation, auriculatone, a natural product firstly obtained from Aster auriculatus, has demonstrated a potent protective effect against APAP-induced hepatotoxicity in HL-7702 cells. However, the poor water solubility and low bioavailability restrict its application. Auriculatone sulfate (AS) is a sulfated derivative of auriculatone with highly improved water-solubility. Hepatoprotective effects against APAP-induced liver injury (AILI) showed that intragastric pretreatment with AS at 50 mg/kg almost completely prevented mice against APAP-induced increases of serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and ATPase. Histological results showed that AS could protect the liver tissue damage. In addition, AS pretreatment not only significantly retained hepatic malondialdehyde and the activities of glutathione, superoxide dismutase, and glutathione peroxidase at normal levels, but also markedly suppressed the increase of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 levels in mouse liver caused by overdose APAP. Immunohistochemical analysis showed that AS obviously attenuated the expression of CD45 and HNE in liver tissue. Further mechanisms of action investigation showed that inhibition of cytochrome P450 3A11 (CYP 3A11) and CYP2E1 enzymatic activities (but not that of CYP1A2) was responsible for APAP bioactivation. In conclusion, AS showed a hepatoprotective effect against AILI through alleviating oxidative stress and inflammation and inhibiting CYP-mediated APAP bioactivation. It may be an effective hepatoprotective agent for AILI and other forms of human liver disease.
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Moshaie-Nezhad P, Faed Maleki F, Hosseini SM, Yahyapour M, Iman M, Khamesipour A. Hepatoprotective and antioxidant effects of Hedera helix extract on acetaminophen induced oxidative stress and hepatotoxicity in mice. Biotech Histochem 2019; 94:313-319. [DOI: 10.1080/10520295.2019.1566569] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
- P. Moshaie-Nezhad
- Faculty of Veterinary Medicine, Babol Branch, Islamic Azad University, Babol, Iran
| | - F. Faed Maleki
- Department of Pharmacology, Babol Branch, Islamic Azad University, Babol, Iran
| | - S. M. Hosseini
- Department of Pathology, Babol Branch, Islamic Azad University, Babol, Iran
| | - M. Yahyapour
- Faculty of Veterinary Medicine, Babol Branch, Islamic Azad University, Babol, Iran
| | - M. Iman
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - A. Khamesipour
- Center for Research and Training in Skin Diseases and Leprosy, Tehran University of Medical Sciences, Tehran, Iran
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Subramanya SB, Venkataraman B, Meeran MFN, Goyal SN, Patil CR, Ojha S. Therapeutic Potential of Plants and Plant Derived Phytochemicals against Acetaminophen-Induced Liver Injury. Int J Mol Sci 2018; 19:ijms19123776. [PMID: 30486484 PMCID: PMC6321362 DOI: 10.3390/ijms19123776] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Revised: 09/02/2018] [Accepted: 09/15/2018] [Indexed: 12/18/2022] Open
Abstract
Acetaminophen (APAP), which is also known as paracetamol or N-acetyl-p-aminophenol is a safe and potent drug for fever, pain and inflammation when used at its normal therapeutic doses. It is available as over-the-counter drug and used by all the age groups. The overdose results in acute liver failure that often requires liver transplantation. Current clinical therapy for APAP-induced liver toxicity is the administration of N-acetyl-cysteine (NAC), a sulphydryl compound an approved drug which acts by replenishing cellular glutathione (GSH) stores in the liver. Over the past five decades, several studies indicate that the safety and efficacy of herbal extracts or plant derived compounds that are used either as monotherapy or as an adjunct therapy along with conventional medicines for hepatotoxicity have shown favorable responses. Phytochemicals mitigate necrotic cell death and protect against APAP-induced liver toxicityby restoring cellular antioxidant defense system, limiting oxidative stress and subsequently protecting mitochondrial dysfunction and inflammation. Recent experimental evidences indicat that these phytochemicals also regulate differential gene expression to modulate various cellular pathways that are implicated in cellular protection. Therefore, in this review, we highlight the role of the phytochemicals, which are shown to be efficacious in clinically relevant APAP-induced hepatotoxicity experimental models. In this review, we have made comprehensive attempt to delineate the molecular mechanism and the cellular targets that are modulated by the phytochemicals to mediate the cytoprotective effect against APAP-induced hepatotoxicity. In this review, we have also defined the challenges and scope of phytochemicals to be developed as drugs to target APAP-induced hepatotoxicity.
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Affiliation(s)
- Sandeep B Subramanya
- Department of Physiology, College of Medicine and Health Sciences, PO Box # 17666, United Arab Emirates University, Al Ain 17666, UAE.
| | - Balaji Venkataraman
- Department of Physiology, College of Medicine and Health Sciences, PO Box # 17666, United Arab Emirates University, Al Ain 17666, UAE.
| | - Mohamed Fizur Nagoor Meeran
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, PO Box # 17666, United Arab Emirates University, Al Ain 17666, UAE.
| | - Sameer N Goyal
- Department of Pharmacology, SVKM's Institute of Pharmacy, Dhule, Maharashtra 424 001, India.
- Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dhule, Maharashtra 425 405, India.
| | - Chandragouda R Patil
- Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dhule, Maharashtra 425 405, India.
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, PO Box # 17666, United Arab Emirates University, Al Ain 17666, UAE.
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Moshaei Nezhad P, Iman M, Maleki FF, Khamesipour A. Hepatoprotective effect of Descurainia sophia seed extract against paracetamol-induced oxidative stress and hepatic damage in mice. JOURNAL OF HERBMED PHARMACOLOGY 2018. [DOI: 10.15171/jhp.2018.40] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
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Samarth RM, Samarth M, Matsumoto Y. Medicinally important aromatic plants with radioprotective activity. Future Sci OA 2017; 3:FSO247. [PMID: 29134131 PMCID: PMC5674267 DOI: 10.4155/fsoa-2017-0061] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 08/15/2017] [Indexed: 01/25/2023] Open
Abstract
Aromatic plants are often used as natural medicines because of their remedial and inherent pharmacological properties. Looking into natural resources, particularly products of plant origin, has become an exciting area of research in drug discovery and development. Aromatic plants are mainly exploited for essential oil extraction for applications in industries, for example, in cosmetics, flavoring and fragrance, spices, pesticides, repellents and herbal beverages. Although several medicinal plants have been studied to treat various conventional ailments only a handful studies are available on aromatic plants, especially for radioprotection. Many plant extracts have been reported to contain antioxidants that scavenge free radicals produced due to radiation exposure, thus imparting radioprotective efficacy. The present review focuses on a subset of medicinally important aromatic plants with radioprotective activity.
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Affiliation(s)
- Ravindra M Samarth
- Department of Research, Bhopal Memorial Hospital & Research Centre, Department of Health Research, Government of India, Raisen Bypass Road, Bhopal 462038, India
- ICMR-National Institute for Research in Environmental Health, Kamla Nehru Hospital Building, GMC Campus, Bhopal 462001, India
| | - Meenakshi Samarth
- Faculty of Science, RKDF University, Airport Bypass Road, Gandhi Nagar, Bhopal 462033, India
| | - Yoshihisa Matsumoto
- Tokyo Institute of Technology, Institute of Innovative Research, Laboratory for Advanced Nuclear Energy, N1–30 2–12–1 Ookayama, Meguro-ku, Tokyo 152–8550, Japan
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Ko JW, Park SH, Shin NR, Shin JY, Kim JW, Shin IS, Moon C, Heo JD, Kim JC, Lee IC. Protective effect and mechanism of action of diallyl disulfide against acetaminophen-induced acute hepatotoxicity. Food Chem Toxicol 2017; 109:28-37. [DOI: 10.1016/j.fct.2017.08.029] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 07/30/2017] [Accepted: 08/22/2017] [Indexed: 10/19/2022]
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Li D, Du Y, Yuan X, Han X, Dong Z, Chen X, Wu H, Zhang J, Xu L, Han C, Zhang M, Xia Q. Hepatic hypoxia-inducible factors inhibit PPARα expression to exacerbate acetaminophen induced oxidative stress and hepatotoxicity. Free Radic Biol Med 2017; 110:102-116. [PMID: 28583670 DOI: 10.1016/j.freeradbiomed.2017.06.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Revised: 05/31/2017] [Accepted: 06/01/2017] [Indexed: 01/25/2023]
Abstract
Oxidative stress has a critical role in the pathogenesis of acetaminophen (APAP) induced hepatocellular necrosis, and the identification of novel approaches to attenuate oxidative stress is essential to prevent/revert the disease. This study investigated the role of both HIF-1 and HIF-2 in the pathogenesis of APAP-induced oxidative stress, as well as the underlying mechanisms. In the present study, we initially found that knockout of HIF-1α or HIF-2α reduced APAP toxicity, and double knockout afforded the best protection. APAP treatment led to stabilization of both HIF-1α and HIF-2α in mouse livers. Moreover, the protective effects of HIF deficiency were related to the attenuated oxidative stress. Further experiments proved that PPARα, a master regulator in cellular metabolism accounted for the HIF deficiency-caused protective impact on APAP toxicity. Inactivation of HIFs promoted the expression of peroxisome proliferator-activated receptor α (PPARα) in the liver, which in turn activated nuclear factor erythroid 2-related factor 2 (Nrf2). Knockdown of PPARα or Nrf2 negated the hepatoprotection afforded by HIF deficiency. At last，examination of the PPARα promoter identified a HIF-binding site and HIF-dependent repression of PPARα in hepatocytes by luciferase reporter and EMSA study. Taken together， Our results demonstrate that HIFs are key suppressors of PPARα in the liver, thereby compromising the adaptive defense mechanisms against oxidative stress when confronted with APAP. These findings are important to the etiology and therapeutics of APAP hepatotoxicity. The functional link between HIFs and PPARα may have more implications in liver physiology and other pathologic conditions than APAP injury.
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Affiliation(s)
- Dawei Li
- Department of Transplantation and Hepatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yingdong Du
- Department of Hepatic Surgery, PLA No.107 hospital, Yantai, China
| | - Xiaodong Yuan
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoxiao Han
- Department of Biomaterials, School of Material, University of Manchester, United Kingdom
| | - Zhen Dong
- Transplantation Center of the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaosong Chen
- Department of Transplantation and Hepatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Haoyu Wu
- Department of Transplantation and Hepatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jianjun Zhang
- Department of Transplantation and Hepatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Longmei Xu
- The Central Laboratory of Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Conghui Han
- Department of Urology, Xuzhou Central Hospital, Xuzhou Medical University School of Clinical Medicine, Xuzhou, China
| | - Ming Zhang
- Department of Transplantation and Hepatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Qiang Xia
- Department of Transplantation and Hepatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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Protective effects of diallyl disulfide against acetaminophen-induced nephrotoxicity: A possible role of CYP2E1 and NF-κB. Food Chem Toxicol 2017; 102:156-165. [DOI: 10.1016/j.fct.2017.02.021] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 01/24/2017] [Accepted: 02/14/2017] [Indexed: 01/14/2023]
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Immature mice are more susceptible than adult mice to acetaminophen-induced acute liver injury. Sci Rep 2017; 7:42736. [PMID: 28205631 PMCID: PMC5311972 DOI: 10.1038/srep42736] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 01/13/2017] [Indexed: 02/07/2023] Open
Abstract
Acetaminophen (APAP) overdose induces acute liver injury. The aim of the present study was to analyze the difference of susceptibility between immature and adult mice to APAP-induced acute liver injury. Weanling immature and adult mice were injected with APAP (300 mg/kg). As expected, immature mice were more susceptible than adult mice to APAP-induced acute liver injury. APAP-evoked hepatic c-Jun N-terminal kinase phosphorylation was stronger in immature mice than in adult mice. Hepatic receptor-interacting protein (RIP)1 was obviously activated at APAP-exposed immature and adult mice. Interestingly, hepatic RIP3 activation was more obvious in APAP-treated immature mice than adult mice. Although there was no difference on hepatic GSH metabolic enzymes between immature and adult mice, immature mice were more susceptible than adult mice to APAP-induced hepatic GSH depletion. Of interest, immature mice expressed a much higher level of hepatic Cyp2e1 and Cyp3a11 mRNAs than adult mice. Correspondingly, immature mice expressed a higher level of hepatic CYP2E1, the key drug metabolic enzyme that metabolized APAP into the reactive metabolite NAPQI. These results suggest that a higher level of hepatic drug metabolic enzymes in immature mice than adult mice might contribute to the difference of susceptibility to APAP-induced acute liver injury.
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Sun Q, Wang G, Gao L, Shi L, Qi Y, Lv X, Jin Y. Roles of CYP2e1 in 1,2-dichloroethane-induced liver damage in mice. ENVIRONMENTAL TOXICOLOGY 2016; 31:1430-1438. [PMID: 25926354 DOI: 10.1002/tox.22148] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2014] [Revised: 04/03/2015] [Accepted: 04/11/2015] [Indexed: 06/04/2023]
Abstract
The aim of this study was to explore the roles of cytochrome P450 2E1 (CYP2E1) in 1,2-dichloroethane (1,2-DCE)-induced liver damage. Two parts were included in this study: first, effect of 1,2-DCE on microsomal expression of CYP2E1, and second, potential of an inhibitor of CYP2E1 to reduce 1,2-DCE-induced liver damage. In part one, mice were exposed to 0, 0.225, 0.45, or 0.9 g/m3 1,2-DCE for 10 days, 3.5 h per day through static inhalation. In part two, mice were divided into blank control, solvent control, inhibitor control, 1,2-DCE-poisoned group, and low or high intervention group. In part one, compared to the control, serum alanine aminotransferase (ALT) activities and hepatic malondialdehyde (MDA) levels in 0.9 g/m3 1,2-DCE group, and microsomal CYP2E1 protein expression and activity in both 0.45 and 0.9 g/m3 1,2-DCE groups increased significantly; conversely, hepatic nonprotein sulfhydryl (NPSH) levels in both 0.45 and 0.9 g/m3 1,2-DCE groups and hepatic SOD activities in 0.9 g/m3 1,2-DCE group decreased significantly. In part two, microsomal CYP2E1 protein expression and activity decreased significantly in both low and high intervention groups compared to 1,2-DCE-poisoned group. Along with the changes of CYP2E1, hepatic MDA levels and serum ALT activities decreased; conversely, hepatic NPSH levels and SOD activities increased significantly in high intervention group. Taken together, our results suggested that 1,2-DCE could enhance CYP2E1 protein expression and enzymatic activity, which could cause oxidative damage in liver, serving as an important mechanism underlying 1,2-DCE-induced liver damage. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1430-1438, 2016.
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Affiliation(s)
- Qi Sun
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Gaoyang Wang
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Lanyue Gao
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Lei Shi
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Ying Qi
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Xiuqiang Lv
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Yaping Jin
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, People's Republic of China.
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Murugavel P, Pari L. Effects of diallyl tetrasulfide on cadmium-induced oxidative damage in the liver of rats. Hum Exp Toxicol 2016; 26:527-34. [PMID: 17698948 DOI: 10.1177/0960327107073810] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The protective efficacy of diallyl tetrasulfide (DTS) from garlic on liver injury induced by cadmium (Cd) was investigated. In this study, Cd (3 mg/kg body weight) was administered subcutaneously for 3 weeks to induce toxicity. DTS was administered orally (10, 20 and 40 mg/kg body weight) for 3 weeks with subcutaneous (sc) injection of Cd. Cd-induced liver damage was evidenced from increased activities of serum hepatic enzymes, namely aspartate transaminase, alanine transaminase, alkaline phosphatase and lactate dehydrogenase, with significant elevation of lipid peroxidation indices (thiobarbituric acid reactive substances and hydroperoxides) and protein carbonyl groups in the liver. Rats subjected to Cd toxicity also showed a decline in the levels of total thiols, reduced glutathione (GSH), vitamin C and vitamin E, accompanied by an increased accumulation of Cd, and significantly decreased activities of superoxide dismutase, catalase (CAT), glutathione peroxidase, glutathione-S-transferase (GST), glutathione reductase, and glucose-6-phosphate dehydrogenase in the liver. Administration of DTS at 40 mg/kg body weight significantly normalised the activities of hepatic marker enzymes, compared to other doses of DTS (10 and 20 mg/kg body weight). In addition, DTS (40 mg/kg body weight) significantly reduced the accumulation of Cd and the level of lipid peroxidation, and restored the level of antioxidant defense in the liver. Histological studies also showed that administration of DTS to Cd-treated rats resulted in a marked improvement of hepatocytes morphology with mild portal inflammation. Our results suggest that DTS might play a vital role in protecting Cd-induced oxidative damage in the liver. Human & Experimental Toxicology(2007) 26, 527—534
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Affiliation(s)
- P Murugavel
- Department of Biochemistry, Faculty of Science, Annamalai University, Annamalainagar 608002, Tamil Nadu, India
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Effect of infusion of spices into the oil vs. combined malaxation of olive paste and spices on quality of naturally flavoured virgin olive oils. Food Chem 2016; 202:221-8. [DOI: 10.1016/j.foodchem.2016.02.005] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 12/22/2015] [Accepted: 02/01/2016] [Indexed: 01/29/2023]
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Liu X, Zhang J, Zhang C, Yang B, Wang L, Zhou J. The inhibition of cytochrome P450 2A13-catalyzed NNK metabolism by NAT, NAB and nicotine. Toxicol Res (Camb) 2016; 5:1115-1121. [PMID: 30090417 DOI: 10.1039/c6tx00016a] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 04/24/2016] [Indexed: 11/21/2022] Open
Abstract
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is considered to be the most carcinogenic of the four tobacco-specific nitrosamines (TSNAs) and it needs to be metabolically activated to exert its carcinogenic effect on humans. For the simultaneous intake of NNK and other compounds with similar molecular structures in the context of tobacco smoke, whether (R,S)-N-nitrosoanatabine (NAT), (R,S)-N-nitrosoanabasine (NAB) and nicotine contribute to the inhibitory potency of the cytochrome P450 (CYP) enzyme-catalyzed NNK metabolism or not needs to be investigated. In the in vitro study, 4-oxo-4-(3-pyridyl) butanal (OPB), 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) and 4-oxo-4-(3-pyridyl) butanoic acid (OPBA) were established as the products of the CYP2A13-catalyzed NNK metabolism and the kinetic parameters were calculated from the Michaelis-Menten equation. Addition of NAT, NAB or nicotine resulted in a competitive inhibition for the NNK metabolism catalyzed by CYP2A13. The inhibition constant Ki values were calculated to be 0.21 μM (NAT), 0.23 μM (NAB) and 8.51 μM (nicotine) for OPB formation; 0.71 μM (NAT), 0.87 μM (NAB) and 25.01 μM (nicotine) for HPB formation and 0.36 μM (NAT), 0.50 μM (NAB) and 6.57 μM (nicotine) for OPBA formation, respectively. In addition, the study of the transformation of the three metabolites revealed OPB was not only an end product but also an intermediate product of the CYP2A13-catalyzed NNK metabolism. These results suggest that structurally similar tobacco constituents with weak or no carcinogenicity influence the metabolic activation of NNK, which interferes with its carcinogenicity to some extent.
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Affiliation(s)
- Xingyu Liu
- Shanghai Tobacco Group Corporation , 99 Wansheng South Street , Tongzhou District , Beijing 101121 , China
| | - Jie Zhang
- Shanghai Tobacco Group Corporation , 99 Wansheng South Street , Tongzhou District , Beijing 101121 , China
| | - Chen Zhang
- Shanghai Tobacco Group Corporation , 99 Wansheng South Street , Tongzhou District , Beijing 101121 , China
| | - Bicheng Yang
- Jiangxi Provincial Maternal and Child Health Hospital , 318 Bayi Road , Nanchang 330006 , Jiangxi , China
| | - Limeng Wang
- Dalian Institute of Chemical Physics , University of Chinese Academy of Sciences , 457 Zhongshan Road , Dalian 116023 , Liaoning , China.,Zhengzhou Tobacco Research Institute , 2 Fengyang Road , Zhengzhou 450001 , Henan , China
| | - Jun Zhou
- Shanghai Tobacco Group Corporation , 99 Wansheng South Street , Tongzhou District , Beijing 101121 , China
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Protective effect of allyl methyl disulfide on acetaminophen-induced hepatotoxicity in mice. Chem Biol Interact 2016; 249:71-7. [DOI: 10.1016/j.cbi.2016.03.008] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 02/08/2016] [Accepted: 03/02/2016] [Indexed: 01/21/2023]
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18
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Wang Y, Jiang Y, Fan X, Tan H, Zeng H, Wang Y, Chen P, Huang M, Bi H. Hepato-protective effect of resveratrol against acetaminophen-induced liver injury is associated with inhibition of CYP-mediated bioactivation and regulation of SIRT1-p53 signaling pathways. Toxicol Lett 2015; 236:82-9. [PMID: 25956474 DOI: 10.1016/j.toxlet.2015.05.001] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2015] [Revised: 04/29/2015] [Accepted: 05/03/2015] [Indexed: 12/22/2022]
Abstract
Resveratrol (RES) has been shown to possess many pharmacological activities including protective effect against liver damage induced by hepatotoxins. In the present study, the hepato-protective effect of RES against acetaminophen (APAP)-induced liver injury in mice and the involved mechanisms was investigated. This study clearly demonstrated that administration of RES three days before APAP treatment significantly alleviated APAP-induced hepatotoxicity, as evidenced by morphological, histopathological, and biochemical assessments such as GSH content and serum ALT/AST activity. Treatment with RES resulted in significant inhibition of CYP2E1, CYP3A11, and CYP1A2 activities, and then caused significant inhibition of the bioactivation of APAP into toxic metabolite NAPQI. Pretreatment with RES significantly reduced APAP-induced JNK activation to protect against mitochondrial injury. Additionally, RES treatment significantly induced SIRT1 and then negatively regulated p53 signaling to induce cell proliferation-associated proteins including cyclin D1, CDK4, and PCNA to promote hepatocyte proliferation. This study demonstrated that RES prevents APAP-induced hepatotoxicity by inhibition of CYP-mediated APAP bioactivation and regulation of SIRT1, p53, cyclin D1 and PCNA to facilitate liver regeneration following APAP-induced liver injury.
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Affiliation(s)
- Ying Wang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Yiming Jiang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Xiaomei Fan
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Huasen Tan
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Hang Zeng
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Yongtao Wang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Pan Chen
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Min Huang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Huichang Bi
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
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Jiang Y, Fan X, Wang Y, Chen P, Zeng H, Tan H, Gonzalez FJ, Huang M, Bi H. Schisandrol B protects against acetaminophen-induced hepatotoxicity by inhibition of CYP-mediated bioactivation and regulation of liver regeneration. Toxicol Sci 2014; 143:107-15. [PMID: 25319358 DOI: 10.1093/toxsci/kfu216] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Schisandra sphenanthera is a traditional hepato-protective Chinese medicine and Schisandrol B (SolB) is one of its major active constituents. In this study, the protective effect of SolB against APAP-induced acute hepatotoxicity in mice and the involved mechanisms were investigated. Morphological and biochemical assessments clearly demonstrated a protective effect of SolB against APAP-induced liver injury. SolB pretreatment significantly attenuated the increases in alanine aminotransferase and aspartate aminotransferase activity, and prevented elevated hepatic malondialdehyde formation and the depletion of mitochondrial glutathione (GSH) in a dose-dependent manner. SolB also dramatically altered APAP metabolic activation by inhibiting the activities of CYP2E1 and CYP3A11, which was evidenced by significant inhibition of the formation of the oxidized APAP metabolite NAPQI-GSH. A molecular docking model also predicted that SolB had potential to interact with the CYP2E1 and CYP3A4 active sites. In addition, SolB abrogated APAP-induced activation of p53 and p21, and increased expression of liver regeneration and antiapoptotic-related proteins such as cyclin D1 (CCND1), PCNA, and BCL-2. This study demonstrated that SolB exhibited a significant protective effect toward APAP-induced liver injury, potentially through inhibition of CYP-mediated APAP bioactivation and regulation of the p53, p21, CCND1, PCNA, and BCL-2 to promote liver regeneration.
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Affiliation(s)
- Yiming Jiang
- *School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Xiaomei Fan
- *School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Ying Wang
- *School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Pan Chen
- *School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Hang Zeng
- *School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Huasen Tan
- *School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Frank J Gonzalez
- *School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Min Huang
- *School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Huichang Bi
- *School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
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Kim NH, Lee S, Kang MJ, Jeong HG, Kang W, Jeong TC. Protective Effects of Diallyl Sulfide against Thioacetamide-Induced Toxicity: A Possible Role of Cytochrome P450 2E1. Biomol Ther (Seoul) 2014; 22:149-54. [PMID: 24753821 PMCID: PMC3975471 DOI: 10.4062/biomolther.2014.016] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Revised: 02/28/2014] [Accepted: 03/06/2014] [Indexed: 01/08/2023] Open
Abstract
Effects of diallyl sulfide (DAS) on thioacetamide-induced hepatotoxicity and immunotoxicity were investigated. When male Sprague-Dawley rats were treated orally with 100, 200 and 400 mg/kg of DAS in corn oil for three consecutive days, the activity of cytochrome P450 (CYP) 2E1-selective p-nitrophenol hydroxylase was dose-dependently suppressed. In addition, the activities of CYP 2B-selective benzyloxyresorufin O-debenzylase and pentoxyresorufin O-depentylase were significantly induced by the treatment with DAS. Western immunoblotting analyses also indicated the suppression of CYP 2E1 protein and/or the induction of CYP 2B protein by DAS. To investigate a possible role of metabolic activation by CYP enzymes in thioacetamide-induced hepatotoxicity, rats were pre-treated with 400 mg/kg of DAS for 3 days, followed by a single intraperitoneal treatment with 100 and 200 mg/kg of thioacetamide in saline for 24 hr. The activities of serum alanine aminotransferase and aspartate aminotransferase significantly elevated by thioacetamide were protected in DAS-pretreated animals. Likewise, the suppressed antibody response to sheep erythrocytes by thioacetamide was protected by DAS pretreatment in female BALB/c mice. Taken together, our present results indicated that thioacetamide might be activated to its toxic metabolite(s) by CYP 2E1, not by CYP 2B, in rats and mice.
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Affiliation(s)
- Nam Hee Kim
- College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea
| | - Sangkyu Lee
- College of Pharmacy, Kyungpook National University, Daegu 702-701, Republic of Korea
| | - Mi Jeong Kang
- College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea
| | - Hye Gwang Jeong
- College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea
| | - Wonku Kang
- College of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea
| | - Tae Cheon Jeong
- College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea
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21
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Patra A, Mandal A, Roy S, Mandal S, Mondal KC, Nandi DK. Protective effect of selected urease positive Lactobacillus strains on acetaminophen induced uremia in rats. ACTA ACUST UNITED AC 2014. [DOI: 10.1016/j.bionut.2014.02.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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22
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Mostafa RM, Moustafa YM, Mirghani Z, AlKusayer GM, Moustafa KM. Antioxidant effect of garlic (Allium sativum) and black seeds (Nigella sativa) in healthy postmenopausal women. SAGE Open Med 2013; 1:2050312113517501. [PMID: 26770698 PMCID: PMC4687760 DOI: 10.1177/2050312113517501] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 11/27/2013] [Indexed: 11/17/2022] Open
Abstract
Objectives: The objective of this study is to investigate the antioxidant effects of garlic extract and crude black seeds’ consumption on blood oxidant/antioxidant levels in healthy postmenopausal women. Methods: In total, 30 healthy postmenopausal women (mean age = 50.31 ± 4.23 years) participated. They ingested two garlic soft gels per day (each is equivalent to 1000 mg of fresh garlic bulb) and crude black seed grounded to powder in a dose of 3 g/day for 8 weeks. Oxidant (malondialdehyde) activity in plasma and antioxidants superoxide dismutase and glutathione peroxidase activities in erythrocytes were studied. Results: Significant low levels of plasma malondialdehyde with increased erythrocyte glutathione peroxidase and superoxide dismutase activities. Discussion: Menopause is associated with an increase in oxidative stress and a decrease in some antioxidant parameters. Consumption of garlic extracts and crude black seeds may have a beneficial effect on improved balance between blood oxidants and antioxidants in healthy postmenopausal women.
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Affiliation(s)
- Randa M Mostafa
- Basic Medical Sciences Department, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Yasser M Moustafa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
| | - Zien Mirghani
- Basic Medical Sciences Department, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Ghader M AlKusayer
- Department of Obstetric and Gynecology, The University of British Columbia, Vancouver, BC, Canada
| | - Kareem M Moustafa
- Department of Clinical Sciences, College of Medicine, Sharjah University, United Arab Emirates
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23
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Metabolomics evaluation of the effects of green tea extract on acetaminophen-induced hepatotoxicity in mice. Food Chem Toxicol 2013; 62:707-21. [PMID: 24080264 DOI: 10.1016/j.fct.2013.09.025] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Revised: 08/29/2013] [Accepted: 09/17/2013] [Indexed: 12/27/2022]
Abstract
Green tea has been purported to have beneficial health effects including protective effects against oxidative stress. Acetaminophen (APAP) is a widely used analgesic drug that can cause acute liver injury in overdose situations. These studies explored the effects of green tea extract (GTE) on APAP-induced hepatotoxicity in liver tissue extracts using ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry and nuclear magnetic resonance spectroscopy. Mice were orally administered GTE, APAP or GTE and APAP under three scenarios. APAP alone caused a high degree of hepatocyte necrosis associated with increases in serum transaminases and alterations in multiple metabolic pathways. The time of GTE oral administration relative to APAP either protected against or potentiated the APAP-induced hepatotoxicity. Dose dependent decreases in histopathology scores and serum transaminases were noted when GTE was administered prior to APAP; whereas, the opposite occurred when GTE was administered after APAP. Similarly, metabolites altered by APAP alone were less changed when GTE was given prior to APAP. Significantly altered pathways included fatty acid metabolism, glycerophospholipid metabolism, glutathione metabolism, and energy pathways. These studies demonstrate the complex interaction between GTE and APAP and the need to employ novel analytical strategies to understand the effects of dietary supplements on pharmaceutical compounds.
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24
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Munday R. Harmful and beneficial effects of organic monosulfides, disulfides, and polysulfides in animals and humans. Chem Res Toxicol 2011; 25:47-60. [PMID: 22004350 DOI: 10.1021/tx200373u] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Many organic sulfides (mono-, di-, and polysulfides) are present in our environment. Simple derivatives are produced by some plants and animals, while complex sulfides are secondary metabolites of several genera of bacteria and fungi. Sulfides play an important role in the smell and taste of food, and many such compounds are used as food flavorings. Some sulfides are toxic, and there is evidence that such toxicity is caused by the ability of these substances to generate reactive oxygen species. Some sulfides, however, have been shown to protect against toxicants and carcinogens. These beneficial effects are believed to involve, at least in part, the ability of sulfides to inhibit the enzymatic activation of pro-toxicants and to increase tissue activities of enzymes that protect against electrophiles. Some sulfides also have potential as cancer chemotherapeutics. In this review, the toxic and beneficial effects of sulfides in animals are described, and the possible value of sulfides in cancer chemoprotection and cancer chemotherapy is discussed.
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Affiliation(s)
- Rex Munday
- AgResearch , Ruakura Research Centre, Private Bag 3123, Hamilton, New Zealand.
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25
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Argüello-García R, Medina-Campos ON, Pérez-Hernández N, Pedraza-Chaverrí J, Ortega-Pierres G. Hypochlorous acid scavenging activities of thioallyl compounds from garlic. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2010; 58:11226-11233. [PMID: 20942486 DOI: 10.1021/jf102423w] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
The hypochlorous acid (HOCl) scavenging capacities of 10 garlic compounds containing modifications in the thioallyl group (-S-CH2CH ═ CH2) were determined by a catalase protection assay, and the corresponding structure-activity relationships using molecular descriptors were calculated. This scavenging activity was enhanced by increasing the number of S atoms or by the alanyl group (-CH2CH-NH2-COOH) and decreased in the absence of the C ═ C bond or in the presence of a sulfoxide group in the thioallyl group. Interestingly, S-allylcysteine and its corresponding sulfoxide (alliin) showed the highest and lowest HOCl-scavenging capacities, respectively. Quantitative modeling by multiple regression analysis and partial least-squares projections showed that the topological descriptor polar surface area and two electronic properties, namely, highest occupied molecular orbital and total energy, contributed mainly to variations in the HOCl scavenging activity of thioallyl compounds. These observations provide new insights on the antioxidant mechanism of garlic derivatives in processes involving HOCl production.
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Affiliation(s)
- Raúl Argüello-García
- Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados-IPN, 07360 Mexico City, Mexico
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26
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Nencini C, Franchi GG, Cavallo F, Micheli L. Protective effect of Allium neapolitanum Cyr. versus Allium sativum L. on acute ethanol-induced oxidative stress in rat liver. J Med Food 2010; 13:329-35. [PMID: 20192846 DOI: 10.1089/jmf.2008.0180] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
This study investigated the protective effect of Allium neapolitanum Cyr., a spontaneous species of the Italian flora, compared with garlic (Allium sativum L.) on liver injury induced by ethanol in rats. Male albino Wistar rats were orally treated with fresh Allium homogenates (leaves or bulbs, 250 mg/kg) daily for 5 days, whereas controls received vehicle only. At the end of the experimental 5-day period, the animals received an acute ethanol dose (6 mL/kg, i.p.) 2 hours before the last Allium administration and were sacrificed 6 hours after ethanol administration. The activities of catalase (CAT), superoxide dismutase (SOD), and glutathione reductase (GR) and the levels of malondialdehyde (MDA), ascorbic acid (AA), and reduced (GSH) and oxidized glutathione in liver tissue were determined. Administration of both Allium species for 5 days (leaves or bulbs) led to no statistical variation of nonenzymatic parameters versus the control group; otherwise Allium treatment caused an increase of GSH and AA levels compared with the ethanol group and a diminution of MDA levels, showing in addition that A. neapolitanum bulb had the best protective effect. Regarding to enzymatic parameters, GR and CAT activities were enhanced significantly compared with the ethanol group, whereas SOD activity showed a trend different from other parameters estimated. However, the treatment with both Allium species followed by acute ethanol administration reestablished the nonenzymatic parameters similar to control values and enhanced the activities of the enzymes measured. These results suggest that fresh Allium homogenates (leaves or bulbs) possess antioxidant properties and provide protection against ethanol-induced liver injury.
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Affiliation(s)
- Cristina Nencini
- Dipartimento di Farmacologia Giorgio Segre, Università di Siena, Siena, Italy
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27
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Zeng T, Xie KQ. The Differential Modulation on Cytochrome P450 Enzymes by Garlic Components. FOOD REVIEWS INTERNATIONAL 2010. [DOI: 10.1080/87559129.2010.496023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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28
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Eu JB, Kim SO, Seoung TJ, Choi SG, Cho SH, Choi CY. Protective Effect of Theanine on the Acetaminophen-induced Hepatotoxicity. ACTA ACUST UNITED AC 2010. [DOI: 10.3746/jkfn.2010.39.3.350] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Shord SS, Shah K, Lukose A. Drug-botanical interactions: a review of the laboratory, animal, and human data for 8 common botanicals. Integr Cancer Ther 2010; 8:208-27. [PMID: 19815591 DOI: 10.1177/1534735409340900] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Many Americans use complementary and alternative medicine (CAM) to prevent or alleviate common illnesses, and these medicines are commonly used by individuals with cancer.These medicines or botanicals share the same metabolic and transport proteins, including cytochrome P450 enzymes (CYP), glucuronosyltransferases (UGTs), and P-glycoprotein (Pgp), with over-the-counter and prescription medicines increasing the likelihood of drug-botanical interactions.This review provides a brief description of the different proteins, such as CYPs, UGTs, and Pgp.The potential effects of drug-botanical interactions on the pharmacokinetics and pharmacodynamics of the drug or botanical and a summary of the more common models used to study drug metabolism are described.The remaining portion of this review summarizes the data extracted from several laboratory, animal, and clinical studies that describe the metabolism, transport, and potential interactions of 8 selected botanicals. The 8 botanicals include black cohosh, Echinacea, garlic, Gingko biloba, green tea, kava, milk thistle, and St John's wort; these botanicals are among some of the more common botanicals taken by individuals with cancer.These examples are included to demonstrate how to interpret the different studies and how to use these data to predict the likelihood of a clinically significant drug-botanical interaction.
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Affiliation(s)
- Stacy S Shord
- College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
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Das J, Ghosh J, Manna P, Sil PC. Taurine protects acetaminophen-induced oxidative damage in mice kidney through APAP urinary excretion and CYP2E1 inactivation. Toxicology 2010; 269:24-34. [PMID: 20067817 DOI: 10.1016/j.tox.2010.01.003] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2009] [Revised: 12/21/2009] [Accepted: 01/05/2010] [Indexed: 11/29/2022]
Abstract
Acute exposure of acetaminophen (APAP), a widely used analgesic and antipyretic drug, causes severe renal damage and no specific agent has been reported so far that plays any beneficial role in this organ pathophysiology. In the present study, the protective role of taurine on APAP-induced nephrotoxicity was investigated in mice. In order to induce acute nephrotoxicity, APAP was administered at a single dose of 2g/kg body weight orally to male adult albino mice of Swiss strain. APAP exposure for 24h significantly increased plasma level of blood urea nitrogen (BUN), creatinine, uric acid, TNF-alpha, NO production, urinary gamma-glutamyl transpeptidase (gamma-GT) activity, total urinary protein and urinary glucose level accompanied by a decrease in Na(+)-K(+)-ATPase activity. Moreover, APAP administration significantly increased MDA, protein carbonylation, GSSG level, intracellular ROS production and cytochrome P450 enzyme (CYPP450) activity. The same exposure decreased GSH level, ferric reducing/antioxidant power (FRAP) as well as the activities of antioxidant enzymes indicating that APAP-induced renal damage was mediated through oxidative stress. Besides, APAP exposure significantly reduced mitochondrial membrane potential and induced up-regulation of CYP2E1 in renal tissues although JNK did not play any significant role in this APAP-induced renal pathophysiology. Caspase 9/3 immunoblot and DNA fragmentation analyses showed that APAP-induced renal cell damage was mostly necrotic in nature, although some apoptosis also occurred simultaneously. Taurine treatment both pre and post (150 mg/kg body weight for 3 days, orally) to APAP exposure, however, significantly reduced APAP-induced nephrotoxicity through its antioxidant properties, urinary excretion of APAP and suppression of CYP2E1. Results suggest that taurine might be a potential therapeutic candidate against APAP-induced acute nephrotoxicity.
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Affiliation(s)
- Joydeep Das
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, West Bengal, India
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31
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Zeng T, Zhang CL, Song FY, Han XY, Xie KQ. The modulatory effects of garlic oil on hepatic cytochrome P450s in mice. Hum Exp Toxicol 2009; 28:777-83. [DOI: 10.1177/0960327109353057] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
In order to probe into the effects of garlic oil (GO) on the hepatic CYP2E1, CYP1A2 and CYP3A, male Kun-Ming mice were treated with GO (100 mg/kg body weight) or corn oil for 1 day or consecutive 60 days, respectively, and then the protein expressions and the activities of the enzymes were examined. GO did not alter the physical activities of mice and did not induce lesion to the liver. However, it dramatically inhibited the activities and protein levels of hepatic CYP2E1 and 1A2, but not CYP3A. In addition, we noticed that the inhibition of CYP2E1 and 1A2 by GO was more potent in group of 1 day treatment than those in group of 60 days treatment. Compared with the respective control value, the protein levels of CYP2E1 were decreased by 87.40% (p < .01) and 62.26% (p < .01) by 1 day and 60 days of GO treatment, respectively, while the CYP1A2 protein levels were decreased by 70.76% (p < .01) and 41.49% (p < .01), respectively. These data indicated that the mice could adapt to the prolonged treatment, which might be one reasonable explanation for the conflicting data in the literature. The CYP2E1 and 1A2 suppression might contribute to its hepatoprotection, and data about CYP3A indicated that GO was unlikely to alter the metabolism of the concomitantly used drugs.
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Affiliation(s)
- Tao Zeng
- Institute of Toxicology, Shandong University, Shandong, Jinan, P.R. China
| | - Cui-Li Zhang
- Institute of Toxicology, Shandong University, Shandong, Jinan, P.R. China
| | - Fu-Yong Song
- Institute of Toxicology, Shandong University, Shandong, Jinan, P.R. China
| | - Xiao-Ying Han
- Institute of Toxicology, Shandong University, Shandong, Jinan, P.R. China, College of life science, Shandong Normal University, Shandong, Jinan, P.R. China
| | - Ke-Qin Xie
- Institute of Toxicology, Shandong University, Shandong, Jinan, P.R. China,
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Mahler GJ, Esch MB, Glahn RP, Shuler ML. Characterization of a gastrointestinal tract microscale cell culture analog used to predict drug toxicity. Biotechnol Bioeng 2009; 104:193-205. [PMID: 19418562 DOI: 10.1002/bit.22366] [Citation(s) in RCA: 167] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The lining of the gastrointestinal (GI) tract is the largest surface exposed to the external environment in the human body. One of the main functions of the small intestine is absorption, and intestinal absorption is a route used by essential nutrients, chemicals, and pharmaceuticals to enter the systemic circulation. Understanding the effects of digestion on a drug or chemical, how compounds interact with and are absorbed through the small intestinal epithelium, and how these compounds affect the rest of the body is critical for toxicological evaluation. Our goal is to create physiologically realistic in vitro models of the human GI tract that provide rapid, inexpensive, and accurate predictions of the body's response to orally delivered drugs and chemicals. Our group has developed an in vitro microscale cell culture analog (microCCA) of the GI tract that includes digestion, a mucus layer, and physiologically realistic cell populations. The GI tract microCCA, coupled with a multi-chamber silicon microCCA representing the systemic circulation, is described and challenged with acetaminophen. Proof of concept experiments showed that acetaminophen passes through and is metabolized by the in vitro intestinal epithelium and is further metabolized by liver cells, resulting in liver cell toxicity in a dose-dependent manner. The microCCA response is also consistent with in vivo measurements in mice. The system should be broadly useful for studies on orally delivered drugs or ingestion of chemicals with potential toxicity.
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Affiliation(s)
- Gretchen J Mahler
- School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York 14853, USA
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Wu YL, Piao DM, Han XH, Nan JX. Protective effects of salidroside against acetaminophen-induced toxicity in mice. Biol Pharm Bull 2008; 31:1523-9. [PMID: 18670083 DOI: 10.1248/bpb.31.1523] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The protective effect of salidroside (SDS) isolated from Rhodiola sachalinensis A. BOR. (Crassulaceae), was investigated in acetaminophen (APAP)-induced hepatic toxicity mouse model in comparison to N-acetylcysteine (NAC). Drug-induced hepatotoxicity was induced by an intraperitoneal (i.p.) injection of 300 mg/kg (sub-lethal dose) of APAP. SDS was given orally to mice at a dose of 50 or 100 mg/kg 2 h before the APAP administration in parallel with NAC. Mice were sacrificed 12 h after the APAP injection to determine aspartate aminotransferase (AST), alanine aminotransferase (ALT), and tumor necrosis factor-alpha (TNF-alpha) levels in serum and glutathione (GSH) depletion, malondialdehyde (MDA) accumulation, and caspase-3 expression in liver tissues. SDS significantly protected APAP-induced hepatotoxicity for SDS improved mouse survival rates better than NAC against a lethal dose of APAP and significantly blocked not only APAP-induced increases of AST, ALT, and TNF-alpha but also APAP-induced GSH depletion and MDA accumulation. Histopathological and immunohistochemical analyses also demonstrated that SDS could reduce the appearance of necrosis regions as well as caspase-3 and hypoxia inducible factor-1alpha (HIF-1alpha) expression in liver tissue. Our results indicated that SDS protected liver tissue from the APAP-induced oxidative damage via preventing or alleviating intracellular GSH depletion and oxidation damage, which suggested that SDS would be a potential antidote against APAP-induced hepatotoxicity.
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Affiliation(s)
- Yan-Ling Wu
- Key Laboratory of Organism Functional Factors of the Changbai Mountain, College of Pharmacy, Yanbian University, Jilin Province, China
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Fakurazi S, Hairuszah I, Nanthini U. Moringa oleifera Lam prevents acetaminophen induced liver injury through restoration of glutathione level. Food Chem Toxicol 2008; 46:2611-5. [PMID: 18514995 DOI: 10.1016/j.fct.2008.04.018] [Citation(s) in RCA: 100] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2008] [Revised: 04/11/2008] [Accepted: 04/11/2008] [Indexed: 12/27/2022]
Abstract
Initiation of acetaminophen (APAP) toxicities is believed to be promoted by oxidative stress during the event of overdosage. The aim of the present study was to evaluate the hepatoprotective action of Moringa oleifera Lam (MO), an Asian plant of high medicinal value, against a single high dose of APAP. Groups of five male Sprague-Dawley rats were pre-administered with MO (200 and 800 mg/kg) prior to a single dose of APAP (3g/kg body weight; p.o). Silymarin was used as an established hepatoprotective drug against APAP induced liver injury. The hepatoprotective activity of MO extract was observed following significant histopathological analysis and reduction of the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in groups pretreated with MO compared to those treated with APAP alone. Meanwhile, the level of glutathione (GSH) was found to be restored in MO-treated animals compared to the groups treated with APAP alone. These observations were comparable to the group pretreated with silymarin prior to APAP administration. Group that was treated with APAP alone exhibited high level of transaminases and ALP activities besides reduction in the GSH level. The histological hepatocellular deterioration was also evidenced. The results from the present study suggested that the leaves of MO can prevent hepatic injuries from APAP induced through preventing the decline of glutathione level.
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Affiliation(s)
- S Fakurazi
- Pharmacology Unit, Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
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Pari L, Murugavel P, Sitasawad SL, Kumar KS. Cytoprotective and antioxidant role of diallyl tetrasulfide on cadmium induced renal injury: An in vivo and in vitro study. Life Sci 2007; 80:650-8. [PMID: 17125799 DOI: 10.1016/j.lfs.2006.10.013] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2006] [Revised: 10/06/2006] [Accepted: 10/18/2006] [Indexed: 11/29/2022]
Abstract
Cadmium (Cd) is an environmental and industrial pollutant that affects various organs in humans and animals. A body of evidence has accumulated implicating the free radical generation with subsequent oxidative stress in the biochemical and molecular mechanisms of Cd toxicity. Since kidney is the critical target of Cd toxicity, we carried out this study to investigate the effects of diallyl tetrasulfide (DTS), an organosulfur compound derived from garlic on Cd induced toxicity in the kidney of rats and also in the kidney cell line (vero cells). In experimental rats, subcutaneous administration of Cd (3 mg/kg bw/day) for 3 weeks induced renal damage, which was evident from significantly increased levels of serum urea and creatinine with significant decrease in creatinine clearance. A markedly increased levels of lipid peroxidation markers (thiobarbituric acid reactive substances and lipid hydroperoxides) and protein carbonyl contents with significant decrease in nonenzymic antioxidants (total sulphydryl groups, reduced glutathione, vitamin C and vitamin E) and enzymic antioxidants (superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase) as well as glutathione metabolizing enzymes (glutathione reductase, and glucose-6-phosphate dehydrogenase) were also observed in Cd intoxicated rats. Coadministration of DTS (40 mg/kg bw/day) and Cd resulted in the reversal of the kidney function accompanied by a significant decrease in lipid peroxidation and increase in the antioxidant defense system. In vitro studies with vero cells showed that incubation of DTS (5-50 microg/ml) with Cd (10 microM) significantly reduced the cell death induced by Cd. DTS at 40 microg/ml effectively blocked the cell death and lipid peroxidation induced by Cd (10 microM) indicating its cytoprotective property. Further, the flow cytometric assessment on the level of intracellular reactive oxygen species using a fluorescent probe 2', 7'-dichlorofluorescein diacetate (DCF-DA) confirmed the Cd induced intracellular oxidative stress in vero cells, which was significantly suppressed by DTS (40 microg/ml). The histopathological studies in the kidney of rats also showed that DTS (40 mg/kg bw/day) markedly reduced the toxicity of Cd and preserved the architecture of renal tissue. The present study suggests that the cytoprotective potential of DTS in Cd toxicity might be due to its antioxidant and metal chelating properties, which could be useful for achieving optimum effects in Cd induced renal damage.
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Affiliation(s)
- L Pari
- Department of Biochemistry, Faculty of Science, Annamalai University, Annamalainagar -- 608002, Tamilnadu, India.
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36
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Murugavel P, Pari L, Sitasawad SL, Kumar S, Kumar S. Cadmium induced mitochondrial injury and apoptosis in vero cells: Protective effect of diallyl tetrasufide from garlic. Int J Biochem Cell Biol 2007; 39:161-70. [PMID: 16971165 DOI: 10.1016/j.biocel.2006.07.013] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2006] [Revised: 07/21/2006] [Accepted: 07/27/2006] [Indexed: 10/24/2022]
Abstract
Oxidative stress and mitochondrial injury has been implicated in cadmium-induced apoptosis. In this study, we examined the protective effect of diallyl tetrasulfide from garlic on cadmium induced oxidative stress and apoptosis in vero cells. Exposure of vero cells to cadmium (10 microM) for 18 h showed the apoptotic events such as loss of cell viability, alterations in nuclear morphology and decreased mitochondrial membrane potential with significantly increased levels of reactive oxygen species (super oxide anion and hydrogen peroxide). Treatment of vero cells with cadmium (10 microM) and diallyl tetrasulfide (5-50 microg/ml) showed that diallyl tetrasulfide attenuated the cadmium-induced suppression of cell viability in a dose dependent manner and highly significant effect was observed at 40 microg/ml. The nuclei morphological analysis with 4',6-diamidino-2-phenylindole staining confirmed that diallyl tetrasulfide at 40 microg/ml prevented the Cd (10 microM) induced apoptosis. Flow cytometric analysis with 2',7'-dichlorofluorencein diacetate showed that the inhibitory effect of diallyl tetrasulfide (10-40 microg/ml) on reactive oxygen species generation parallel with its effect on cell viability. In addition, diallyl tetrasulfide (40 microg/ml) remarkably reduced the cadmium-induced accumulation of superoxide radical and hydrogen peroxide with in cells. Further, diallyl tetrasulfide significantly protected the cadmium-induced decrease in mitochondrial membrane potential, an indicator of mitochondrial function. Our study suggest that diallyl tetrasulfide affect the reactive oxygen species generation induced by cadmium, and possesses a novel protective effect on the cytolethality associated with mitochondrial injury, which contributes to the antiapoptotic effect of diallyl tetrasulfide against cadmium.
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Affiliation(s)
- Ponnusamy Murugavel
- Department of Biochemistry, Faculty of Science, Annamalai University, Annamalainagar 608002, Tamilnadu, India
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37
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Papetti A, Daglia M, Grisoli P, Dacarro C, Gregotti C, Gazzani G. Anti- and pro-oxidant activity of Cichorium genus vegetables and effect of thermal treatment in biological systems. Food Chem 2006. [DOI: 10.1016/j.foodchem.2005.03.036] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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38
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Hsu CC, Lin CC, Liao TS, Yin MC. Protective effect of s-allyl cysteine and s-propyl cysteine on acetaminophen-induced hepatotoxicity in mice. Food Chem Toxicol 2006; 44:393-7. [PMID: 16181716 DOI: 10.1016/j.fct.2005.08.012] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2005] [Revised: 08/08/2005] [Accepted: 08/12/2005] [Indexed: 11/27/2022]
Abstract
In vivo protective effects of s-allyl cysteine (SAC) and s-propyl cysteine (SPC) against acetaminophen-induced hepatotoxicity in Balb/cA mice were studied. SAC and SPC at 1g/L were added into drinking water for four weeks and followed by acetaminophen treatment. Acetaminophen treatment significantly depleted glutathione content, increased oxidation stress and elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities (P < 0.05); however, the intake of SAC or SPC significantly alleviated glutathione depletion and the elevation of ALT and AST, enhanced glutathione peroxidase activity, and lowered malondialdehyde formation (P < 0.05). Plasma levels of C-reactive protein (CRP), von Willebrand factor (vWF), IL-6, IL-10 and TNF-alpha were significantly increased by acetaminophen treatment (P < 0.05); and SAC or SPC intake significantly suppressed acetaminophen-induced elevation of CRP, vWF and the three cytokines (P < 0.05). Acetaminophen treatment also significantly increased plasminogen activator inhibitor-1 (PAI-1) activity and plasma fibrinogen level, and decreased antithrombin III (AT-III) and protein C activities (P < 0.05). SAC or SPC intake alleviated AT-III and protein C reduction (P < 0.05); but did not affect PAI-1 activity and plasma fibrinogen level (P > 0.05). These data suggest that SAC and SPC are potential multiple-protective agents against acetaminophen-induced hepatotoxicity.
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Affiliation(s)
- Cheng-Chin Hsu
- Department of Nutritional Science, Chung Shan Medical University, Taichung, Taiwan, ROC
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39
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Pal R, Vaiphei K, Sikander A, Singh K, Rana SV. Effect of garlic on isoniazid and rifampicin-induced hepatic injury in rats. World J Gastroenterol 2006; 12:636-9. [PMID: 16489682 PMCID: PMC4066101 DOI: 10.3748/wjg.v12.i4.636] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the hepatoprotective effect of garlic on liver injury induced by isoniazid (INH) and rifampicin (RIF).
METHODS: Wistar rats weighing 150-200 g were treated orally with 50 mg/kg of INH and RIF daily each for 28 d. For hepatoprotective studies, 0.25 g/kg per day of freshly prepared garlic homogenate was administered orally half an hour before the INH+RIF doses. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin were estimated on d 0, 14, 21, and 28 in all the rats. Histological analysis was carried out to assess the injury to the liver. Lipid peroxidation (LPO) as a marker of oxidative stress and non-protein thiols (glutathione) for antioxidant levels were measured in liver homogenate.
RESULTS: The treatment of rats with INH+RIF (50 mg/kg per day each) induced hepatotoxicity in all the treated animals as judged by elevated serum ALT, AST, and bilirubin levels, presence of focal hepatocytic necrosis (6/8) and portal triaditis (8/8). Garlic simultaneously administered at a dose of 0.25 g/kg per day prevented the induction of histopathological injuries in INH+RIF co-treated animals, except in 4 animals, which showed only moderate portal triaditis. The histological changes correlated with oxidative stress in INH+RIF treated animals. The group which received 0.25 g/kg per day garlic homogenate along with INH+RIF showed higher levels of glutathione (P < 0.05) and low levels of LPO (P < 0.05) as compared to INH+RIF treated group.
CONCLUSION: Freshly prepared garlic homogenate protects against INH+RIF-induced liver injury in experimental animal model.
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Affiliation(s)
- Ravinder Pal
- Department of Gastor PGIMER, Chd, House No. 137, Sector 15-A, Chandigarh 160015, India
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40
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Rose P, Whiteman M, Moore PK, Zhu YZ. Bioactive S-alk(en)yl cysteine sulfoxide metabolites in the genus Allium: the chemistry of potential therapeutic agents. Nat Prod Rep 2005; 22:351-68. [PMID: 16010345 DOI: 10.1039/b417639c] [Citation(s) in RCA: 252] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
S-Alk(en)yl cysteine sulfoxides are odourless, non-protein sulfur amino acids typically found in members of the family Alliaceae and are the precursors to the lachrymatory and flavour compounds found in the agronomically important genus Allium. Traditionally, Allium species, particularly the onion (Allium cepa) and garlic (A. sativum), have been used for centuries in European, Asian and American folk medicines for the treatment of numerous human pathologies, however it is only recently that any significant progress has been made in determining their mechanisms of action. Indeed, our understanding of the role of Allium species in human health undoubtedly comes from the combination of several academic disciplines including botany, biochemistry and nutrition. During tissue damage, S-alk(en)yl cysteine sulfoxides are converted to their respective thiosulfinates or propanethial-S-oxide by the action of the enzyme alliinase (EC 4.4.1.4). Depending on the Allium species, and under differing conditions, thiosulfinates can decompose to form additional sulfur constituents including diallyl, methyl allyl, and diethyl mono-, di-, tri-, tetra-, penta-, and hexasulfides, the vinyldithiins and (E)- and (Z)-ajoene. Recent reports have shown onion and garlic extracts, along with several principal sulfur constituents, can induce phase II detoxification enzymes like glutathione-S-transferases (EC 2.5.1.18) and quinone reductase (QR) NAD(P)H: (quinine acceptor) oxidoreductase (EC 1.6.99.2) in mammalian tissues, as well as also influencing cell cycle arrest and apoptosis in numerous in vitro cancer cell models. Moreover, studies are also beginning to highlight a role of Allium-derived sulfur compounds in cardiovascular protection. In this review, we discuss the chemical diversity of S-alk(en)yl cysteine sulfoxide metabolites in the context of their biochemical and pharmacological mechanisms.
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Affiliation(s)
- Peter Rose
- Department of Biochemistry, National University of Singapore, 8 Medical Drive, Singapore, 117597.
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41
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Hsu CC, Huang CN, Hung YC, Yin MC. Five cysteine-containing compounds have antioxidative activity in Balb/cA mice. J Nutr 2004; 134:149-52. [PMID: 14704308 DOI: 10.1093/jn/134.1.149] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Balb/cA mice were used to study the in vivo effect of N-acetyl cysteine, S-allyl cysteine, S-ethyl cysteine, S-methyl cysteine and S-propyl cysteine, all derived from garlic, on glutathione (GSH) concentration and catalase and glutathione peroxidase (GPX) activities in plasma, kidney and liver. Cysteine was used for comparison. The effects of these compounds on the levels of fibronectin, triglyceride (TG), cholesterol and alpha-tocopherol were also evaluated. Cysteine or cysteine-containing compounds were added to drinking water at 1 g/L. After 4 wk of treatment, GSH levels in kidney and liver were greater (P<0.05) than in controls. Cysteine decreased catalase and GPX activities in liver, and enhanced both Fe2+- and glucose-induced lipid oxidation in plasma, kidney and liver compared with the control group (P<0.05). However, the administration of the five cysteine-containing compounds enhanced catalase and GPX activities in kidney and liver, and reduced Fe2+- and glucose-induced lipid oxidation in plasma, kidney and liver compared with the control and cysteine-treated groups (P<0.05). Intake of the five cysteine-containing compounds reduced fibronectin, TG and cholesterol concentrations in plasma and liver, and increased the alpha-tocopherol concentration in plasma, kidney and liver compared with the control and cysteine-treated groups (P<0.05). The five cysteine-containing compounds derived from garlic had marked effects on antioxidant enzymes and spared alpha-tocopherol in mice. Furthermore, these compounds reduced fibronectin, TG and cholesterol concentrations in plasma. These data indicate that these compounds have a range of protective effects for cardiovascular disease prevention or therapy.
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Affiliation(s)
- Cheng-chin Hsu
- Department of Nutritional Science, Chungshan Medical University, Taichung City, Taiwan
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42
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Bedda S, Laurent A, Conti F, Chéreau C, Tran A, Tran-Van Nhieu J, Jaffray P, Soubrane O, Goulvestre C, Calmus Y, Weill B, Batteux F. Mangafodipir prevents liver injury induced by acetaminophen in the mouse. J Hepatol 2003; 39:765-72. [PMID: 14568259 DOI: 10.1016/s0168-8278(03)00325-8] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS Acute liver failure (ALF), characterized by massive hepatocyte necrosis, is often caused by drug poisoning, particularly with acetaminophen (APAP). Hepatocyte necrosis is consecutive to glutathione depletion by NAPQI, a metabolite of APAP, and to mitochondrial damages caused by reactive oxygen species (ROS) overproduction. Considering the structure of Mangafodipir, a contrast agent currently used in magnetic resonance imaging of the liver, we hypothesized that this molecule could exert an antioxidant activity and be possibly used as a treatment of APAP-induced ALF. METHODS/RESULTS Mangafodipir is endowed with superoxide dismutase, catalase, and glutathione reductase activities. It can inhibit ROS production by hepatocytes in culture, and protect those cells from oxidative stresses induced by exposure to xanthine oxidase, H(2)O(2), or UV light. Moreover, preventive or curative administration of Mangafodipir to mice with APAP-induced ALF significantly increases survival rates, and abrogates aspartate aminotransferase elevation and histological damage. CONCLUSIONS Those data point out the potential interest of Mangafodipir in the treatment of toxic ALF in humans.
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Affiliation(s)
- Sassia Bedda
- Laboratoire d'Immunologie, UPRES 1833, Faculté Cochin, Pavillon Hardy, Université Paris V, AP-HP, 75679 Paris Cedex 14, France
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43
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Effect of grape antioxidant dietary fiber on the total antioxidant capacity and the activity of liver antioxidant enzymes in rats. Nutr Res 2003. [DOI: 10.1016/s0271-5317(03)00131-3] [Citation(s) in RCA: 174] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Banerjee SK, Mukherjee PK, Maulik SK. Garlic as an antioxidant: the good, the bad and the ugly. Phytother Res 2003; 17:97-106. [PMID: 12601669 DOI: 10.1002/ptr.1281] [Citation(s) in RCA: 271] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Garlic has played an important dietary and medicinal role throughout the history of mankind. In some Western countries, the sale of garlic preparations ranks with those of leading prescription drugs. The therapeutic efficacy of garlic encompasses a wide variety of ailments, including cardiovascular, cancer, hepatic and microbial infections to name but a few. However, the elucidation of its mechanism for therapeutic action has proved to be more elusive and a unifying theory, which could account for its reported multifarious activities, is yet to emerge. Reactive oxygen species (ROS) seem to be at the core of many disease processes and it is an attractive and convenient hypothesis that garlic might exert its activities through modulatory effects on ROS. A literature search on garlic and its antioxidant potential churned up a surprisingly large amount of data, some of it good, some bad and some of its definitely ugly. Various preparations of garlic, mainly aged garlic extract (AGE), have been shown to have promising antioxidant potential. However, the presence of more than one compounds in garlic, with apparently opposite biological effects, has added to the complexity of the subject. Raw garlic homogenate has been reported to exert antioxidant potential but higher doses have been shown to be toxic to the heart, liver and kidney. So where do we stand today on this issue of garlic? Is garlic always good for health? How safe is it? Is it necessary to isolate the antioxidant compounds for its medicinal use in a more effective way? These issues are addressed in this review.
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Affiliation(s)
- S K Banerjee
- Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India
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45
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Krause RJ, Glocke SC, Elfarra AA. Sulfoxides as urinary metabolites of S-allyl-L-cysteine in rats: evidence for the involvement of flavin-containing monooxygenases. Drug Metab Dispos 2002; 30:1137-42. [PMID: 12228191 DOI: 10.1124/dmd.30.10.1137] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
S-Allyl-L-cysteine (SAC), a component of garlic and a metabolite of allyl halides, is a known substrate for multiple flavin-containing monooxygenases (FMOs). In the current study, we characterize the in vivo SAC metabolism by investigating the presence of SAC, N-acetyl-S-allyl-L-cysteine (NASAC), and their corresponding sulfoxides in the urine of rats given SAC (200 or 400 mg/kg i.p.). In some experiments, rats were given aminooxyacetic acid (AOAA), an inhibitor of cysteine conjugate beta-lyase, or methimazole, an alternative FMO substrate, 30 min prior to treatment with 200 mg/kg SAC. Nearly 40 to 50% of the dose was recovered in the 24-h collection period. In all treatment groups, the majority of the metabolites were excreted within 8 h. The major metabolites detected were NASAC and NASAC sulfoxide (NASACS; nearly 30-40% and 5-10% of the dose, respectively). Only small amounts of the dose (approximately 1.5%) were recovered as SAC and SAC sulfoxide (SACS). Methimazole pretreatment significantly reduced amounts of both SACS and NASACS detected in the urine when compared with rats given SAC only, whereas AOAA pretreatment had no effect. In vitro assays using rat liver microsomes were also carried out to compare the sulfoxidation rates of SAC and NASAC. The results showed that SAC was much more readily oxidized than NASAC. Collectively, the results provide evidence for the involvement of FMOs in the in vivo metabolism of SAC and that SAC is a much better substrate for FMOs than its corresponding mercapturic acid.
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Affiliation(s)
- Renee J Krause
- Department of Comparative Biosciences and the Center for Molecular and Environmental Toxicology, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
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46
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Yang CS. Inhibition of carcinogenesis and toxicity by dietary constituents. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2002; 500:541-50. [PMID: 11764996 DOI: 10.1007/978-1-4615-0667-6_83] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- C S Yang
- Laboratory for Cancer Research, College of Pharmacy, Rutgers, The State University of New Jersey Piscataway, 08854-8020, USA
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47
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Lin MC, Wang EJ, Lee C, Chin KT, Liu D, Chiu JF, Kung HF. Garlic inhibits microsomal triglyceride transfer protein gene expression in human liver and intestinal cell lines and in rat intestine. J Nutr 2002; 132:1165-8. [PMID: 12042427 DOI: 10.1093/jn/132.6.1165] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Epidemiologic studies have suggested that fresh garlic has lipid-lowering activity. Because the microsomal triglyceride transfer protein (MTP) plays a pivotal role in the assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins, we evaluated the effect of garlic on the expression of the MTP gene in vitro in cell lines and in vivo in rats. Fresh garlic extract (FGE) reduced MTP mRNA levels in both the human hepatoma HepG2 and intestinal carcinoma Caco-2 cells in dose-dependent fashion; significant reductions were detected with 3 g/L FGE. Maximal 72 and 59% reductions, respectively, were observed with 6 g/L FGE. To evaluate the in vivo effect of garlic on MTP gene expression, rats were given a single oral dose of fresh garlic homogenate (FGH), with hepatic and intestinal MTP mRNA measured 3 h after dosing. Rats fed FGH had significantly (46% of the control) lower intestinal MTP mRNA levels compared with the control rats, whereas hepatic MTP mRNA levels were not affected. These results suggest a new mechanism for the hypolipidemic effect of fresh garlic. Long-term dietary supplementation of fresh garlic may exert a lipid-lowering effect partly through reducing intestinal MTP gene expression, thus suppressing the assembly and secretion of chylomicrons from intestine to the blood circulation.
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Affiliation(s)
- Marie C Lin
- Institute of Molecular Biology, Open Laboratory of Chemical Biology, Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Hong Kong, China.
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Sahu SC. Dual role of organosulfur compounds in foods: a review. JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH. PART C, ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS 2002; 20:61-76. [PMID: 12734054 DOI: 10.1081/gnc-120005388] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Organosulfur compounds present in natural food are generally considered as beneficial for health because of their antioxidant and anticarcinogenic properties. This has led to their excessive and long-term consumption. However, there is also evidence that these compounds demonstrate toxicity and adverse health effects suggesting their potential dual biological roles. Thus, they can act as double-edged biological swords.
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Affiliation(s)
- Saura C Sahu
- Division of In Vitro and Biochemical Toxicology, Office of Applied Research and Safety Assessment, U.S. Food and Drug Administration, Laurel, MD 20708, USA.
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Sumioka I, Matsura T, Yamada K. Therapeutic effect of S-allylmercaptocysteine on acetaminophen-induced liver injury in mice. Eur J Pharmacol 2001; 433:177-85. [PMID: 11755151 DOI: 10.1016/s0014-2999(01)01503-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
S-allylmercaptocysteine is one of the water-soluble organosulfur compounds in ethanol extracts of garlic (Allium sativum L.). We had demonstrated earlier that treatment with S-allylmercaptocysteine before acetaminophen administration protects mice against acetaminophen-induced hepatotoxicity. In this study, we examined the therapeutic effect of S-allylmercaptocysteine treatment after acetaminophen administration. A single dose of S-allylmercaptocysteine (200 mg/kg, p.o.) to mice 0.5 h after acetaminophen administration (500 mg/kg, p.o.) significantly suppressed both the increase in plasma alanine aminotransferase activity and the hepatic necrosis, and also reduced acetaminophen-induced mortality from 43% to 0%. These data indicate that S-allylmercaptocysteine is useful as an antidote for acetaminophen overdose. S-allylmercaptocysteine significantly suppressed hepatic cytochrome P450 2E1 (CYP2E1) activity and induction of inducible 70-kDa heat shock protein, a marker of acetaminophen arylation of protein. These results suggest that S-allylmercaptocysteine exerts its protective effect by inhibition of CYP2E1 activity, which leads to the suppression of acetaminophen arylation of hepatic protein.
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Affiliation(s)
- I Sumioka
- Healthcare Research Institute, Wakunaga Pharmaceutical Co., Ltd., 1624 Shimokotachi, Koda-cho, Takata-gun, Hiroshima 739-1195, Japan
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Lee KJ, You HJ, Park SJ, Kim YS, Chung YC, Jeong TC, Jeong HG. Hepatoprotective effects of Platycodon grandiflorum on acetaminophen-induced liver damage in mice. Cancer Lett 2001; 174:73-81. [PMID: 11675154 DOI: 10.1016/s0304-3835(01)00678-4] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The protective effects of an aqueous extract from the roots of Platycodon grandiflorum A. DC (Campanulaceae), Changkil (CK), on acetaminophen (APAP)-induced hepatotoxicities and the possible protective mechanisms involved were investigated in mice. Pretreatment with CK prior to the administration of APAP significantly prevented the increase in serum alanine aminotransferase and aspartate aminotransferase activity and hepatic lipid peroxidation in a dose-dependent manner. APAP-induced hepatotoxicity was also essentially prevented as evidenced by liver histopathology. Hepatic glutathione levels and glutathione-S-transferase activities were not affected by treatment with CK alone, but pretreatment with CK protected the APAP-induced depletion of hepatic glutathione levels. The effects of CK on cytochrome P450 (P450) 1A2 and 2E1, the major isozymes involved in APAP bioactivation, were investigated. In microsomal incubations, CK effectively inhibited P450 lA2-dependent methoxyresorufin O-deethylase activities and the P450 2E1-dependent p-nitrophenol and aniline hydroxylase. The results suggest that the protective effects of CK against the APAP-induced hepatotoxicity may, at least in part, be due to its ability to block P450-mediated APAP bioactivation.
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Affiliation(s)
- K J Lee
- Department of Biology, Chonnam National University, Kwangju, South Korea
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