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Zhuang XM, Zhong YH, Xiao WB, Li H, Lu C. Identification and characterization of psoralen and isopsoralen as potent CYP1A2 reversible and time-dependent inhibitors in human and rat preclinical studies. Drug Metab Dispos 2013; 41:1914-22. [PMID: 23975028 DOI: 10.1124/dmd.113.053199] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025] Open
Abstract
Naturally occurring furanocoumarin compounds psoralen (PRN) and isopsoralen (IPRN) are bioactive constituents found in herbaceous plants. They are widely used as active ingredients in several Chinese herbal medicines. In this study, the CYP1A2 inhibitory potential of PRN and IPRN was investigated in rats in vitro and in vivo as well as in human liver microsomes. Both compounds exhibited reversible and time-dependent inhibition toward rat microsomal cyp1a2. The IC(50), k(inact), and K(I) values were 10.4 ± 1.4 μM, 0.060 ± 0.002 min(-1), and 1.13 ± 0.12 μM for PRN, and 7.1 ± 0.6 μM, 0.10 ± 0.01 min(-1), and 1.95 ± 0.31 μM for IPRN, respectively. In human liver microsomal incubations, potent reversible CYP1A2 inhibition was observed for both compounds, with IC(50) values of 0.26 ± 0.01 μM and 0.22 ± 0.03 μM for PRN and IPRN, respectively. However, time-dependent inhibition was only observed for IPRN, with kinact and KI values of 0.050 ± 0.002 min(-1) and 0.40 ± 0.06 μM, respectively. Coadministration with PRN or IPRN significantly inhibited cyp1a2 activity in rats, with the area under the curve (AUC) of phenacetin increasing more than 5-fold. Simcyp simulation predicted that PRN would cause 1.71- and 2.12-fold increases in the phenacetin AUC in healthy volunteers and smokers, respectively. IPRN, on the other hand, would result in 3.24- and 5.01-fold increases in phenacetin AUCs in healthy volunteers and smokers, respectively. These findings represent the first detailed report comparing the potential drug-drug interactions of PRN and IPRN, and provide useful information for balancing safe and efficacious doses of PRN and IPRN.
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Affiliation(s)
- Xiao-Mei Zhuang
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Beijing Institute of Pharmacology and Toxicology, Beijing, China (X.-M.Z., Y.-H.Z., W.-B.X., H.L.); and Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts (C.L.)
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Zubairy YF, Patil VW, Benjamin T, Jangam D, Bijle MNA, Patil S. Effect of methylxanthines (coffee/tea consumers) on oral precancer and oral cancer patients with smoking and smokeless tobacco habits. J Contemp Dent Pract 2012; 13:745-758. [PMID: 23403995 DOI: 10.5005/jp-journals-10024-1221] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
AIM To study, whether the consumption of regular tea/coffee (methylxanthines) increases the risk of oral cancer in patients with smoking and smokeless tobacco habits. MATERIALS AND METHODS This study was conducted on a total of 90 oral cancer and precancerous patients, from western Maharashtra (India) males in the age group of 20 to 45 years who were with smoking and smokeless tobacco habits; also regular tea/coffee consumers were subjected to biochemical parameters such as aspartate transaminase (AST) and alanine transaminase (ALT) from saliva and serum of patients with oral precancer (submucous fibrosis, leukoplakia) and oral cancer patients and compared with 90-age and sex-matched controls. Individuals consent was taken to measure their biochemical parameters, by using Hafkenscheid method in whole saliva and serum. Statistical analysis of variance (ANOVA) with Tukey's correction for multiple group comparisons was performed using Student t-test. RESULTS Results show, that a statistically significant increase in value (p < 0.05) in ALT, AST in both saliva and serum was observed in precancerous and oral cancer patients among the study group as compared to the control group. CONCLUSION In the present study, there was increase in the levels of ALT, AST enzymes in both saliva and serum levels in the study group as compared to the control group which was statistically significant (p < 0.05) suggesting that long-term exposure of methylxanthines results in impairment of salivary gland antioxidant system which may affect the anticarcinogenic action of saliva. CLINICAL SIGNIFICANCE Oral fluids may be utilized effectively to study the variations in the biochemical constituents of saliva of leukoplakia, submucous fibrosis and oral cancer patients.
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Affiliation(s)
- Yasmeen F Zubairy
- Department of Biochemistry, Grant Medical College and Sir JJ Groups of Hospital, Mumbai, Maharashtra, India
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Helyar SG, Patel B, Headington K, Assal ME, Chatterjee PK, Pacher P, Mabley JG. PCB-induced endothelial cell dysfunction: role of poly(ADP-ribose) polymerase. Biochem Pharmacol 2009; 78:959-65. [PMID: 19549508 PMCID: PMC2756480 DOI: 10.1016/j.bcp.2009.06.019] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2009] [Revised: 06/11/2009] [Accepted: 06/15/2009] [Indexed: 12/14/2022]
Abstract
Polychlorinated biphenyls (PCBs) are persistent environmental pollutants implicated in the development of pro-inflammatory events critical in the pathology of atherosclerosis and cardiovascular disease. PCB exposure of endothelial cells results in increased cellular oxidative stress, activation of stress and inflammatory pathways leading to increased expression of cytokines and adhesion molecules and ultimately cell death, all of which can lead to development of atherosclerosis. To date no studies have been performed to examine the direct effects of PCB exposure on the vasculature relaxant response which if impaired may predispose individuals to hypertension, an additional risk factor for atherosclerosis. Overactivation of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) following oxidative/nitrosative stress in endothelial cells and subsequent depletion of NADPH has been identified as a central mediator of cellular dysfunction. The aim therefore was to investigate whether 2,2',4,6,6'-pentachlorobiphenyl (PCB 104) directly causes endothelial cell dysfunction via increased oxidative stress and subsequent overactivation of PARP. Exposure of ex vivo rat aortic rings to PCB 104 impaired the acetylcholine-mediated relaxant response, an effect that was dependent on both concentration and exposure time. In vitro exposure of mouse endothelial cells to PCB 104 resulted in increased cellular oxidative stress through activation of the cytochrome p450 enzyme CYP1A1 with subsequent overactivation of PARP and NADPH depletion. Pharmacological inhibition of CYP1A1 or PARP protected against the PCB 104-mediated endothelial cell dysfunction. In conclusion, the environmental contaminants, PCBs, can activate PARP directly impairing endothelial cell function that may predispose exposed individuals to development of hypertension and cardiovascular disease.
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MESH Headings
- Acetylcholine/pharmacology
- Animals
- Aorta, Thoracic/cytology
- Aorta, Thoracic/drug effects
- Cell Survival/drug effects
- Cells, Cultured
- Cytochrome P-450 CYP1A1/antagonists & inhibitors
- Cytochrome P-450 CYP1A1/metabolism
- Dose-Response Relationship, Drug
- Endothelial Cells/drug effects
- Endothelial Cells/metabolism
- Endothelium, Vascular/cytology
- Endothelium, Vascular/drug effects
- Environmental Pollutants/chemistry
- Environmental Pollutants/pharmacology
- Indicators and Reagents/metabolism
- Male
- Mice
- Molecular Structure
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- NADP/analysis
- NADP/metabolism
- Nitric Oxide/biosynthesis
- Nitroblue Tetrazolium/metabolism
- Oxidants/adverse effects
- Oxidation-Reduction
- Oxidative Stress/drug effects
- Poly(ADP-ribose) Polymerase Inhibitors
- Poly(ADP-ribose) Polymerases/metabolism
- Polychlorinated Biphenyls/chemistry
- Polychlorinated Biphenyls/pharmacology
- Rats
- Rats, Sprague-Dawley
- Time Factors
- Vasodilation/drug effects
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Affiliation(s)
- Simon G. Helyar
- Brighton and Sussex Medical School, Falmer, Brighton BN1 9PH, UK
| | - Bella Patel
- School of Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, Lewes Road, Brighton BN2 4GJ, UK
| | - Kevin Headington
- School of Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, Lewes Road, Brighton BN2 4GJ, UK
| | - Mary El Assal
- School of Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, Lewes Road, Brighton BN2 4GJ, UK
| | - Prabal K. Chatterjee
- School of Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, Lewes Road, Brighton BN2 4GJ, UK
| | - Pal Pacher
- Section on Oxidative Stress Tissue Injury, Laboratory of Physiological Studies, National Institutes of Health/NIAAA, 5625 Fishers Lane, Bethesda, MD 20892-9413, USA
| | - Jon G. Mabley
- School of Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, Lewes Road, Brighton BN2 4GJ, UK
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Yang KH, Lee JH, Lee MG. Effects of CYP inducers and inhibitors on the pharmacokinetics of intravenous theophylline in rats: involvement of CYP1A1/2 in the formation of 1,3-DMU. J Pharm Pharmacol 2008; 60:45-53. [PMID: 18088504 DOI: 10.1211/jpp.60.1.0006] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
The types of hepatic cytochrome P450 (CYP) isozymes responsible for the metabolism of theophylline and for the formation of 1,3-dimethyluric acid (1,3-DMU) in rats in-vivo does not seem to have been studied at the dose ranges of dose-independent metabolic disposition of theophylline in rats (up to 10 mg kg(-1)). Therefore, theophylline (5 mg kg(-1)) was administered i.v. to male Sprague-Dawley rats pretreated with various inducers and inhibitors of CYP isozymes. In rats pretreated with 3-methylcholanthrene (3-MC), orphenadrine or dexamethasone (main inducers of CYP1A1/2, CYP2B1/2 and CYP3A1/2, respectively, in rats), the time-averaged non-renal clearance (CLNR) of theophylline was significantly faster than in their respective controls (1260, 42.7 and 69.0% increases, respectively). However, in rats pretreated with troleandomycin (a major inhibitor of CYP3A1/2 in rats), CLNR was significantly slower than in the controls (50.7% decrease). The 24 h urinary excretion of 1,3-DMU was increased significantly only in rats pretreated with 3-MC. The ratio of area under the curve for 1,3-DMU and theophylline (AUC1,3-DMU/AUCtheophylline) was increased significantly in rats pretreated with 3-MC (160% increase) and decreased significantly in rats pretreated with troleandomycin (50.1% decrease); however, the ratio was not increased in rats pretreated with dexamethasone. These data suggest that theophylline is primarily metabolized via CYP1A1/2, CYP2B1/2, and CYP3A1/2, and that 1,3-DMU is primarily formed via CYP1A1/2, and possibly CYP3A1/2, in rats.
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Affiliation(s)
- Kyung H Yang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea
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Tang J, Sun J, Zhang Y, Li L, Cui F, He Z. Herb-drug interactions: Effect of Ginkgo biloba extract on the pharmacokinetics of theophylline in rats. Food Chem Toxicol 2007; 45:2441-5. [PMID: 17681658 DOI: 10.1016/j.fct.2007.05.023] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2005] [Revised: 03/09/2006] [Accepted: 05/29/2007] [Indexed: 11/17/2022]
Abstract
Herbal medicines have received great attention as alternative medicines in recent years and are also referred to as a dietary supplement or health food. Ginkgo biloba extract (GBE) is one of the most popular herbal medicines. However, little is known about the metabolic interactions between GBE and clinically used drugs. This study attempted to investigate the effect of GBE on the pharmacokinetics of theophylline, a cytochrome P450 (CYP) 1A2 substrate and an important therapeutic agent with narrow therapeutic window used for the treatment of asthma. Commercial GBE (10 or 100 mg/kg, p.o.) or water (control group) was given to rats (6 rats for each group) for 5 consecutive days and on the sixth day theophylline (10 mg/kg) was administered either orally or intravenously. The results showed that pretreatment of rats with GBE resulted in an increase in the total clearance of theophylline of about 30% (GBE 10 mg/kg, P<0.05) and 70% (GBE 100 mg/kg, P<0.01) compared with the control group after intravenous administration of theophylline (10 mg/kg). After oral administration of theophylline (10 mg/kg), the AUC(0-24h) of theophylline was reduced by 40% following pretreatment with GBE (100 mg/kg, P<0.01). These results demonstrate that GBE pretreatment increased CYP1A2 metabolic activity and the clearance of theophylline in rats.
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Affiliation(s)
- Jingling Tang
- Department of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Mailbox 59#, 103 Wenhua Road, Shenyang 110016, China
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Jan WC, Lin LC, Tsai TH. Herb-drug interaction of Evodia rutaecarpa extract on the pharmacokinetics of theophylline in rats. JOURNAL OF ETHNOPHARMACOLOGY 2005; 102:440-5. [PMID: 16099612 DOI: 10.1016/j.jep.2005.07.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2004] [Revised: 03/21/2005] [Accepted: 07/06/2005] [Indexed: 05/04/2023]
Abstract
The extract of Evodia rutaecarpa fruit and its preparation were used for the treatment of gastrointestinal disorders and headache. To assess the possible herb-drug interaction, the ethanol extract of Evodia rutaecarpa fruit (1 and 2 g/kg/day, p.o.) and the herbal preparation Wu-Chu-Yu-Tang (1 and 5 g/kg/day) were given to rats daily for three consecutive days and on the fourth day theophylline was administered (2 mg/kg, i.v.). Theophylline concentration in blood was measured by a microdialysis coupled to a liquid chromatographic system. Pharmacokinetic data were calculated by noncompartmental model. The results indicate that the theophylline level was significantly decreased by the pretreatment with the extract of Evodia rutaecarpa and herbal preparation Wu-Chu-Yu-Tang with dose-related manner. It is suggested that the herb-drug interaction may occur through the induction of the metabolism of theophylline.
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Affiliation(s)
- Woan-Ching Jan
- Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
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Abstract
AIM: To study the influence of inducers BNF and PB on the stere oselective metabolism of propranolol in rat hepatic microsomes.
METHODS: Phase I metabolism of propranolol was studied by using the microsomes induced by BNF and PB and the non-induced microsome as the control. The enzymatic kinetic parameters of propranolol enantiomers were calculated by regression analysis of Lineweaver-Burk plots. Propranolol concentrations we re assayed by HPLC.
RESULTS: A RP-HPLC method was developed to determine propranol ol concentration in rat hepatic microsomes. The linearity equations for R (+)pr opranolol and S (-)propranolol were A = 705.7C + 311.2C (R = 0.9987) and A = 697.2C+311.4C (R = 0.9970) respectively. Recoveries of each enant iomer were 98.9%, 99.5%, 101.0% at 60 μmol/L, 120 μmol/L, 240 μmol/L respectively. At the concentration level of 120 μmol/L, propranolol enantiomers were metabolized at different rates in different microsomes. The concentration ratio R (+)/S (-) of control and PB induced microsomes increased with time, whereas that of microsome induced by BNF decreased. The assayed enzyme parameters were: 1. Km. Control group: R (+)30 ± 8, S (-) 18 ± 5; BNF group: R (+) 34 ± 3, S (-)39 ± 7; PB group: R (+)38 ± 17, S (-) 36 ± 10. 2. Vmax. Control group: R (+)1.5 ± 0.2, S (-)2.9 ± 0.3; BNF group: R (+)3.8 ± 0.3, S (-)3. 3 ± 0.5 ; PB group: R (+)0.07 ± 0.03, S (-)1.94 ± 0. 07. 3. Clint. Control group: R (+)60 ± 3, S (-) 170 ± 30; BNF group: R (+)111.0 ± 1, S (-) 84 ± 5; PB group: R (+)2.0 ± 2, S (-)56.0 ± 1. The enzyme parameters compared with unpaired t tests showed that no stereoselectivity was observed in enzymatic affinity of three microsomes to enantiomers and their catalytic abilities were quite different and had stereoselectivities. Compared with the control, microsome induced by BNF enhanced enzyme activity to propranolol R (+)enantiomer, and microsome induced by PB showed less enzyme activity to propranolol S (-)-enan tiomer which remains the same stereoselectivities as that of the control.
CONCLUSION: Enzyme activity centers of the microsome were changed in composition and regioselectivity after the induction of BNF and PB, and the stereoselectivities of propranolol cytochrome P450 metabolism in rat hepatic microsomes were likely due to the stereoselectivities of the catalyzing function in enzyme. CYP-1A subfamily induced by BNF exhibited pronounced contribution to propranolol metabolism with stereoselectivity to R (+)-enantiomer. CYP-2B subfamily induced by PB exhibited moderate contribution to propranolol metabolism, but still had the stereoselectivity of S (-)-enantiomer.
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Meneguz A, Fortuna S, Lorenzini P, Volpe MT. Influence of urethane and ketamine on rat hepatic cytochrome P450 in vivo. EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY : OFFICIAL JOURNAL OF THE GESELLSCHAFT FUR TOXIKOLOGISCHE PATHOLOGIE 1999; 51:392-6. [PMID: 10445403 DOI: 10.1016/s0940-2993(99)80027-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The aim of this study was to identify the effects of widely used laboratory anaesthetics on cytochrome (CYP) activity in male Sprague Dawley rats in vivo. The anaesthetics used were urethane and ketamine. 7-Ethoxyresorufin (EROD), 7-pentoxyresorufin (PROD), aniline and ethylmorphine were used as substrates for CYP 1A, CYP 2B, CYP 2E1 and CYP 3A, respectively. Urethane increased EROD (CYP 1A) activity by 40 % (p < 0.01), and hydroxylation of aniline (CYP 2E1) by 14 % in the early phase of anaesthesia and by 60 % (p < 0.01) in the later one. Urethane also reduced the demethylation of ethylmorphine by 37 % (p < 0.01), but did not affect CYP 2B activity significantly. Ketamine did not significantly affect CYP 1A, 2B or 2E1. However, it reduced the demethylation of ethylmorphine (i.e. CYP 3A) by 32 % (p < 0.01). From these data, we concluded that a single dose of urethane inhibits CYP 3A but increases CYP 2E1 and CYP 1A, and that a single dose of ketamine inhibits the activity of CYP 3A.
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Affiliation(s)
- A Meneguz
- Department of Biochemical Pharmacology, Istituto Superiore di Sanità, Roma, Italia
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