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Cheraghpour M, Hatami B, Singal AG. Lifestyle and Pharmacologic Approaches to Prevention of Metabolic Dysfunction-associated Steatotic Liver Disease-related Hepatocellular Carcinoma. Clin Gastroenterol Hepatol 2025; 23:685-694.e6. [PMID: 39800201 DOI: 10.1016/j.cgh.2024.09.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 09/19/2024] [Accepted: 09/30/2024] [Indexed: 01/15/2025]
Abstract
Hepatocellular carcinoma (HCC) is a major concern for public health. Fatty liver disease, related to alcohol misuse or metabolic syndrome, has become the leading cause of chronic liver disease and HCC. The strong association between type 2 diabetes mellitus and HCC can be partly attributed to the development of metabolic dysfunction-associated steatotic liver disease (MASLD). There is a strong interest in strategies that may mitigate HCC risk and reduce HCC incidence in this growing population of at-risk individuals. In this review, we describe the pathogenesis of HCC in patients with MASLD and discuss potential emerging pharmacological and lifestyle interventions for MASLD-related HCC. HCC risk has been observed to be lower with healthy lifestyle behaviors, such as healthy dietary patterns (eg, high consumption of vegetables, whole grains, fish and poultry, yogurt, and olive oil, and low consumption of red and processed meats and dietary sugar) and increased physical activity. Selecting an appropriate pharmacologic approach for individuals with MASLD may also decrease the occurrence of HCC. Metformin, PPAR activators, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, aspirin, and statins have all shown promise to reduce the risk of HCC, although guidelines do not recommend their use for the sole purpose of chemoprevention at this time, given a dearth of data defining their risk-benefit ratio.
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Affiliation(s)
- Makan Cheraghpour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
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Huang YS, Tseng SY, Chang TE, Perng CL, Huang YH. Sulfamethoxazole-trimethoprim-induced liver injury and genetic polymorphisms of NAT2 and CYP2C9 in Taiwan. Pharmacogenet Genomics 2021; 31:200-206. [PMID: 34149005 DOI: 10.1097/fpc.0000000000000441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Sulfamethoxazole-trimethoprim (SMX-TMP) is one of the most frequently used antibiotics. SMX is metabolized by N-acetyltransferase (NAT) and cytochrome P450 2C9 (CYP2C9) to nontoxic or toxic intermediates. Little is known about the association between genetic variations of these enzymes and SMX-TMP-induced liver injury (SILI). The aim of this study was to explore the genetic polymorphisms of NAT2 and CYP2C9 and the susceptibility to SILI in a Han Chinese population. METHODS A total of 158 patients with SILI and 145 controls were recruited in this study. PCR-based genotyping with matrix-assisted laser desorption ionization-time of flight was used to assay the major NAT2 and CYP2C9 genotypes including NAT2 rs1495741, rs1041983, rs1801280, CYP2C9 rs1799853, rs1057910 and rs4918758. RESULTS The SILI group had a higher frequency of the NAT2 rs1495741 variant AA genotype and rs1041983 variant TT genotype than the controls (42.4 vs. 25.5%; P = 0.008, and 40.5 vs. 25.5%; P = 0.022, respectively). The SILI group had more slow acetylators than the controls (43.7 vs. 25.5%; P = 0.001). There were no significant differences in the genetic variations of CYP2C9 between the SILI and control groups. After adjusting for confounding factors, the NAT2 slow acetylators still had an increased risk of SILI (adjusted OR: 2.49; 95% confidence interval: 1.46-4.24; P = 0.001), especially in those with hepatocellular and mixed type SILI. CONCLUSIONS NAT2 slow acetylators are associated with a higher risk of SILI in the Han Chinese population. However, CYP2C9 genetic polymorphisms are not associated with the susceptibility to SILI.
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Affiliation(s)
- Yi-Shin Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, and National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan
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Hoehn RS. Racial disparities in hepatocellular carcinoma. Cancer 2021; 127:1369-1370. [PMID: 33629740 DOI: 10.1002/cncr.33376] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 09/25/2020] [Indexed: 01/14/2023]
Affiliation(s)
- Richard S Hoehn
- Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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Abstract
Hepatocellular carcinoma (HCC) occurs in patients with chronic liver damage, inflammation and cirrhosis. The facilitators involved in increasing the HCC risk in the damaged liver are yet to be discovered. Diet and lifestyle have a profound effect on the liver inflammation and HCC. The term “gut liver axis” describes the bidirectional relationship between the liver and the gut, which are both anatomically and functionally related. Chronic liver damage is characterised by increased intestinal permeability that allows the translocation of various components and metabolites from the gut microbiota to the liver, resulting in liver inflammation and fibrosis. In this review, we discuss how diet-induced changes in gut microbiome composition, such as lipopolysaccharide and lipoteichoic acid, and its metabolites, such as bile acids, play a role in the pathogenesis of liver fibrosis and HCC.
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Ma Y, Yang W, Li T, Liu Y, Simon TG, Sui J, Wu K, Giovannucci EL, Chan AT, Zhang X. Meat intake and risk of hepatocellular carcinoma in two large US prospective cohorts of women and men. Int J Epidemiol 2020; 48:1863-1871. [PMID: 31302687 DOI: 10.1093/ije/dyz146] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/28/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Epidemiological evidence on the associations between meat intake and risk of hepatocellular carcinoma (HCC) was limited and inconsistent. METHODS We prospectively examined the association between consumption of meats and meat mutagens with HCC risk using data from the Nurses' Health Study and the Health Professionals Follow-up Study. Cox proportional-hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for known liver-cancer risk factors. RESULTS During up to 32 years of follow-up, we documented 163 incident HCC cases. The HRs of HCC for the highest vs the lowest tertile intake levels were 1.84 (95% CI: 1.16-2.92, Ptrend = 0.04) for processed red meats and 0.61 (95% CI: 0.40-0.91, Ptrend = 0.02) for total white meats. There was a null association between unprocessed red meats and HCC risk (HR = 1.06, 95% CI: 0.68-1.63, Ptrend = 0.85). We found both poultry (HR = 0.60, 95% CI: 0.40-0.90, Ptrend = 0.01) and fish (HR = 0.70, 95% CI: 0.47-1.05, Ptrend = 0.10) were inversely associated with HCC risk. The HR for HCC risk was 0.79 (95% CI: 0.61-1.02) when 1 standard deviation of processed red meats was substituted with an equivalent amount of poultry or fish intake. We also found a suggestive positive association of intake of meat-derived mutagenicity or heterocyclic amines with risk of HCC. CONCLUSIONS Processed red meat intake might be associated with higher, whereas poultry or possibly fish intake might be associated with lower, risk of HCC. Replacing processed red meat with poultry or fish might be associated with reduced HCC risk.
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Affiliation(s)
- Yanan Ma
- School of Public Health, China Medical University, Shenyang, Liaoning, P. R. China.,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Wanshui Yang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.,Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, Anhui, P.R. China
| | - Tricia Li
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Yue Liu
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.,Center for Evidence-Based Chinese Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, P.R. China
| | - Tracey G Simon
- Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.,Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.,Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital, Boston, MA, USA
| | - Jing Sui
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.,Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, P.R. China
| | - Kana Wu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Edward L Giovannucci
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Andrew T Chan
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.,Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.,Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital, Boston, MA, USA
| | - Xuehong Zhang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Shawon MAA, Yousuf MAK, Raheem E, Ahmed S, Dipti TT, Hoque MR, Taniguchi H, Karim MR. Epidemiology, clinical features, and impact of food habits on the risk of hepatocellular carcinoma: A case-control study in Bangladesh. PLoS One 2020; 15:e0232121. [PMID: 32339207 PMCID: PMC7185601 DOI: 10.1371/journal.pone.0232121] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 04/07/2020] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer mortality worldwide. Infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) is the most predominant cause of HCC. Concerns arise for the presence of additional risk factors, as there is still a large proportion of patients without HBV or HCV infection. Previous studies have reported that higher intake of fruits and vegetables and reduced consumption of red/processed meat might play a protective role in HCC etiology, though the nationwide proof is limited. Hence, we studied multiple risk factors including food habit, lifestyle, and clinical implications of HCC patients in Bangladeshi. Demographic, clinical, and biochemical data, as well as data on food habits, were collected in this study. Our results indicated that a high intake of rice (AOR 4.28, 95% CI 1.48 to 14.07, p = 0.011), low intake of fruits (AOR = 4.41 95% CI 1.48-15.46; p = 0.012), leafy vegetables (AOR = 2.80, 95% CI 1.32-6.08; p = 0.008), and fish (AOR = 4.64 95% CI 2.18-10.23; p<0.001) increased the HCC risk. Moreover, a high intake of eggs (AOR = 2.07 95% CI 0.98-4.43; p = 0.058) also showed an increased risk. Roti, non-leafy vegetables, red meat, and tea were found to have no association with HCC risk. This study revealed that food habit patterns and lifestyle may have a profound effect on HCC development among Bangladeshi patients in addition to well established risk factors.
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Affiliation(s)
- M. Al-Amin Shawon
- Laboratory for Cancer Biology, Department of Biotechnology and Genetic Engineering, Jahangirnagar University, Savar, Dhaka, Bangladesh
| | - M. Abul Khair Yousuf
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | | | - Sium Ahmed
- Laboratory for Cancer Biology, Department of Biotechnology and Genetic Engineering, Jahangirnagar University, Savar, Dhaka, Bangladesh
| | - Tyeaba Tasnim Dipti
- Laboratory for Cancer Biology, Department of Biotechnology and Genetic Engineering, Jahangirnagar University, Savar, Dhaka, Bangladesh
| | - Mohammad Razuanul Hoque
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong, Bangladesh
| | - Hiroaki Taniguchi
- Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Jastrzebiec, Magdalenka, Poland
| | - M. Rezaul Karim
- Laboratory for Cancer Biology, Department of Biotechnology and Genetic Engineering, Jahangirnagar University, Savar, Dhaka, Bangladesh
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Desai A, Sandhu S, Lai JP, Sandhu DS. Hepatocellular carcinoma in non-cirrhotic liver: A comprehensive review. World J Hepatol 2019; 11:1-18. [PMID: 30705715 PMCID: PMC6354117 DOI: 10.4254/wjh.v11.i1.1] [Citation(s) in RCA: 194] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 12/22/2018] [Accepted: 01/01/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, which in turns accounts for the sixth most common cancer worldwide. Despite being the 6th most common cancer it is the second leading cause of cancer related deaths. HCC typically arises in the background of cirrhosis, however, about 20% of cases can develop in a non-cirrhotic liver. This particular subgroup of HCC generally presents at an advanced stage as surveillance is not performed in a non-cirrhotic liver. HCC in non-cirrhotic patients is clinically silent in its early stages because of lack of symptoms and surveillance imaging; and higher hepatic reserve in this population. Interestingly, F3 fibrosis in non-alcoholic fatty liver disease, hepatitis B virus and hepatitis C virus infections are associated with high risk of developing HCC. Even though considerable progress has been made in the management of this entity, there is a dire need for implementation of surveillance strategies in the patient population at risk, to decrease the disease burden at presentation and improve the prognosis of these patients. This comprehensive review details the epidemiology, risk factors, clinical features, diagnosis and management of HCC in non-cirrhotic patients and provides future directions for research.
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Affiliation(s)
- Aakash Desai
- Department of Internal Medicine, Case Western Reserve University/MetroHealth Medical Center, Cleveland, OH 44109, United States
| | - Sonia Sandhu
- Department of Hematology and Oncology, Cleveland Clinic/Akron General Medical Center, Akron, OH 44307, United States
| | - Jin-Ping Lai
- Department of Pathology, University of Florida, Gainsville, FL 32611, United States
| | - Dalbir Singh Sandhu
- Division of Gastroenterology and Hepatology, Case Western Reserve University/MetroHealth Medical Center, Cleveland, OH 44109, the United States
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Xu C, Luo L, Yu Y, Zhang Z, Zhang Y, Li H, Cheng Y, Qin H, Zhang X, Ma H, Li Y. Screening therapeutic targets of ribavirin in hepatocellular carcinoma. Oncol Lett 2018; 15:9625-9632. [PMID: 29805683 PMCID: PMC5958667 DOI: 10.3892/ol.2018.8552] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 10/13/2017] [Indexed: 12/16/2022] Open
Abstract
The objective of the present study was to screen the key genes of ribavirin in hepatocellular carcinoma (HCC) and provide novel therapeutic targets for HCC treatment. The mRNA expression datasets of GSE23031 and GSE74656, as well as the microRNA (miRNA) expression dataset of GSE22058 were downloaded from the Gene Expressed Omnibus database. In the GSE23031 dataset, there were three HCC cell lines treated with PBS and three HCC cell lines treated with ribavirin. In the GSE74656 dataset, five HCC tissues and five carcinoma adjacent tissues were selected. In the GSE22058 dataset, 96 HCC tissues and 96 carcinoma adjacent tissues were selected. The differentially expressed genes (DEGs) and differentially expressed miRNAs were identified via the limma package of R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed with the Database for Annotation, Visualization and Integrated Discovery. The target mRNAs of DEMs were obtained with TargetScan. A total of 559 DEGs (designated DEG-Ribavirin) were identified in HCC cells treated with ribavirin compared with PBS and 632 DEGs (designated DEG-Tumor) were identified in HCC tissues compared with carcinoma adjacent tissues. A total of 220 differentially expressed miRNAs were identified in HCC tissues compared with carcinoma adjacent tissues. In addition, 121 GO terms and three KEGG pathways of DEG-Ribavirin were obtained, and 383 GO terms and 25 KEGG pathways of DEG-Tumor were obtained. A total of five key miRNA-mRNA regulated pairs were identified, namely miR-183→CCNB1, miR-96→DEPDC1, miR-96→NTN4, miR-183→NTN4 and miR-145→NTN4. The present study indicated that certain miRNAs (including miR-96, miR-145 and miR-183) and mRNAs (including NAT2, FBXO5, CCNB1, DEPDC1 and NTN4) may be associated with the effects of ribavirin on HCC. Furthermore, they may provide novel therapeutic targets for HCC treatment.
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Affiliation(s)
- Chen Xu
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, P.R. China
| | - Liyun Luo
- Department of Cardiology, The Fifth Affiliated Hospital of Sun Yan-Sen University, Zhuhai, Guangdong 519000, P.R. China
| | - Yongjun Yu
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, P.R. China
| | - Zhao Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, P.R. China
| | - Yi Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, P.R. China
| | - Haimei Li
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, P.R. China
| | - Yue Cheng
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, P.R. China
| | - Hai Qin
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, P.R. China
| | - Xipeng Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, P.R. China
| | - Hongmei Ma
- Department of Nursing, Tianjin Union Medical Center, Tianjin 300121, P.R. China
| | - Yuwei Li
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, P.R. China
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Rim CH. Development of quantitative index evaluating anticancer or carcinogenic potential of diet: the anti-cancer food scoring system 1.0. Nutr Res Pract 2018; 12:52-60. [PMID: 29399297 PMCID: PMC5792257 DOI: 10.4162/nrp.2018.12.1.52] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 12/31/2017] [Accepted: 01/02/2018] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND/OBJECTIVE Cancer is closely related to diet. One of the most reliable reports of the subject is the expert report from the World Cancer Research Fund & American Institute of Cancer Research (WCRF&AICR). However, majority of the studies including above were written with academic terms and in English. The aim of this study is to create a model, named Anti-Cancer Food Scoring System (ACFS), to provide a simple index of the anticancer potential of food. SUBJECTS/METHODS We created ACFS codes of various food groups. The evidence of the ACFS codes was provided by the literature at a level comparable to that suggested in the WCRF&AICR report or from the WCRF&AICR report. The ACFS grade was calculated considering food group, cooking, and normalization. Application was performed for Koreans' 20 common meals, which encompass multinational recipes. RESULT We calculated the ACFS grades of Koreans' 20 common meals. The results were not significantly different from the WCRF&AICR guidelines or information from the National Cancer Information Center of Korea. The grades were briefly interpreted as follows: grade S. ideal for cancer prevention; grade A. good for cancer prevention; grade B, might have anticancer potential; grade C, difficult to be regarded as preventive or carcinogenic; grade D, might against cancer prevention; grade E, probably against cancer prevention. CONCLUSIONS The ACFS provides a simple index of anticancer potential of diets. This indicator can be useful for the people without expertise, and is effective in evaluating the diets including Asian foods. The ACFS can help design of future clinical or nutritional studies of cancer prevention.
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Affiliation(s)
- Chai Hong Rim
- Department of Radiation Oncology, Ansan Hospital, Korea University Medical College, 123, Jeokgeum ro, Danwon-gu, Gyeonggi 15355, Korea
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Koumbi L. Dietary factors can protect against liver cancer development. World J Hepatol 2017; 9:119-125. [PMID: 28217247 PMCID: PMC5295144 DOI: 10.4254/wjh.v9.i3.119] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2016] [Revised: 11/08/2016] [Accepted: 12/02/2016] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is the third leading cause of cancer mortality worldwide with hepatocellular carcinoma (HCC) representing more than 90% of primary liver cancers. Most HCC patients are also suffering from chronic liver disease (CLD). Evidence is emerging that the composition of diet plays an important role in HCC and CLD development and may also have a chemoprotective role. In contrast to other types of cancer, there are few studies investigating the role of diet in hepatocarcinogenesis. From the available data it is evident that high intakes of red meat and dietary sugar positively correlate with HCC occurrence. On the contrary, high consumption of white meat, fish, vegetables, fruits and cereals are inversely associated with HCC risk. This letter discusses the potential role of dietary interventions in the prevention of hepatocarcinogenesis. The increasing HCC incidence and its high fatality are making HCC prevention an urgent matter. Dietary modifications are found to offer protection against HCC, however, new studies from well-designed and large prospective trials are required to confirm these results.
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Alcohol consumption and liver cancer risk: a meta-analysis. Cancer Causes Control 2015; 26:1205-31. [PMID: 26134046 DOI: 10.1007/s10552-015-0615-3] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 06/09/2015] [Indexed: 02/07/2023]
Abstract
PURPOSE Alcohol is a confirmed risk factor of liver cancer. Yet, its dose-response function and synergistic effects with other risk factors remain unclear. METHODS We performed a meta-analysis on publications up to May 2014. A total of 112 publications were identified. The meta-relative risk (mRR) and the dose-response trend were calculated. Tests for heterogeneity, publication bias, and sensitivity analyses were performed. The synergy index (SI) was recorded or calculated, whenever possible. RESULTS Compared to individuals who never drank or drank at very low frequencies, the mRR for ever drinkers was 1.29 (95% confidence interval, CI 1.16-1.42) and 1.46 (95% CI 1.27-1.65) for case-control studies, and 1.07 (95% CI 0.87-1.27) for cohort studies. Being a current drinker was associated with an increased liver cancer risk in case-control studies (mRR = 1.55, 95% CI 0.38-2.73), but not in cohort studies (mRR = 0.86, 95% CI 0.74-0.97). The dose-response relation between alcohol and liver cancer was apparent with RR = 1.08 (95% CI 1.04-1.11) for 12 g/day (~1 drink), 1.54 (95% CI 1.36-1.74) for 50 g/day, 2.14 (95% CI 1.74-2.62) for 75 g/day, 3.21 (95% CI 2.34-4.40) for 100 g/day, and 5.20 (95% CI 3.25-8.29) for 125 g/day of alcohol consumption. There were synergistic effects of alcohol consumption with hepatitis (S = 2.14, 95% CI 1.31-2.98) and with diabetes (S = 3.57, 95% CI 2.29-4.84) on the risk of liver cancer, although this may be subject to publication bias. CONCLUSION Overall, one alcoholic drink per day (~12 g/day) may be associated with a 1.1 times higher liver cancer risk. Further studies on the synergistic effects of alcohol consumption and other major risk factors are warranted.
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Yang Y, Zhang D, Feng N, Chen G, Liu J, Chen G, Zhu Y. Increased intake of vegetables, but not fruit, reduces risk for hepatocellular carcinoma: a meta-analysis. Gastroenterology 2014; 147:1031-42. [PMID: 25127680 DOI: 10.1053/j.gastro.2014.08.005] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Revised: 07/22/2014] [Accepted: 08/09/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The anti-cancer effects of vegetables and fruit have been investigated extensively, but the association between vegetable and fruit consumption and risk of hepatocellular carcinoma (HCC) has not been quantified. We performed a meta-analysis of observational studies to clarify the association. METHODS We identified eligible studies, published from 1956 through May 31, 2014, by searching PubMed, Web of Science, and EMBASE. Random-effects models were used to calculate summary relative risks (RRs) and dose-response analyses were conducted to quantify associations. Heterogeneity among studies was evaluated using Cochran's Q and I(2) statistics. RESULTS A total of 19 studies involving 1,290,045 participants and 3912 cases of HCC were included in the meta-analysis. The summary RR for HCC was 0.72 for individuals with high intake vs low intake of vegetables (95% confidence interval [CI]: 0.63-0.83) and 0.92 with a daily increase in vegetable intake (100 g/d) (95% CI: 0.88-0.95). Subgroup analyses showed that this inverse association did not change regardless of history of hepatitis, alcohol drinking, smoking, or energy intake. The summary RR for HCC among individuals with high vs low intake of fruit was 0.93 (95% CI: 0.80-1.09), and 0.99 with a daily increase in fruit intake (100 g/d) (95% CI: 0.94-1.05). CONCLUSIONS Based on a meta-analysis, increased intake of vegetables, but not fruit, is associated with lower risk for HCC. The risk of HCC decreases by 8% for every 100 g/d increase in vegetable intake. The findings should be confirmed by future studies with validated questionnaires and strict control of confounders.
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Affiliation(s)
- Yang Yang
- Department of Radiation Therapy, Zhejiang Cancer Hospital, Hangzhou, China; Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China.
| | - Dan Zhang
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Na Feng
- Department of Ultrasound, Zhejiang Cancer Hospital, Hangzhou, China
| | - Guochong Chen
- Ningbo Municipal Center for Disease Control and Prevention, Ningbo, China
| | - Jianjiang Liu
- Department of Radiation Therapy, Zhejiang Cancer Hospital, Hangzhou, China; Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China
| | - Guiping Chen
- Department of Surgery, Zhejiang Cancer Hospital, Hangzhou, China
| | - Yuan Zhu
- Department of Radiation Therapy, Zhejiang Cancer Hospital, Hangzhou, China; Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China
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Luo J, Yang Y, Liu J, Lu K, Tang Z, Liu P, Liu L, Zhu Y. Systematic review with meta-analysis: meat consumption and the risk of hepatocellular carcinoma. Aliment Pharmacol Ther 2014; 39:913-22. [PMID: 24588342 DOI: 10.1111/apt.12678] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 11/18/2013] [Accepted: 02/09/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND The association between meat consumption and the risk of hepatocellular carcinoma (HCC) is still inconclusive. AIM To conduct a systematic review and meta-analysis to quantitatively assess the relationship between meat intake and the risk of HCC. METHODS We searched the PubMed, Web of Science and EMBASE databases for relevant studies published before July 2013. The summary relative risks were pooled using the fixed-effects model when no substantial heterogeneity was detected, otherwise, the random-effects model was used. Heterogeneity and publication bias were also analysed. RESULTS Finally, seven cohort studies and 10 case-control studies were included. The pooled relative risks (RRs) of HCC for the highest vs. lowest consumption levels were 1.10 (95% confidence interval, CI: 0.85-1.42) for red meat, 1.01 (95% CI: 0.79-1.28) for processed meat and 0.97 (95% CI: 0.85-1.11) for total meat. Moreover, white meat and fish consumption were found to be inversely associated with HCC risk, the summary RRs were 0.69 (95% CI: 0.58-0.81) and 0.78 (95% CI: 0.67-0.90) respectively, and the results remained quite stable after stratification by the confounding factors. CONCLUSIONS The present meta-analysis indicates that a high level of white meat or fish consumption can reduce the risk of HCC significantly, while intake of red meat, processed meat or total meat is not associated with HCC risk. Our findings suggest that dietary intervention may be a promising approach for prevention of HCC, which still need to be confirmed by further well-designed prospective studies and experimental research.
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Affiliation(s)
- J Luo
- Department of Radiation Therapy, Zhejiang Cancer Hospital, Hangzhou, China
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14
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Yang Y, Wu QJ, Xie L, Chow WH, Rothman N, Li HL, Gao YT, Zheng W, Shu XO, Xiang YB. Prospective cohort studies of association between family history of liver cancer and risk of liver cancer. Int J Cancer 2014; 135:1605-14. [PMID: 24535817 DOI: 10.1002/ijc.28792] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 01/24/2014] [Accepted: 01/29/2014] [Indexed: 12/17/2022]
Abstract
Uncertainty remains on the relationship between a family history of liver cancer and liver cancer risk in prospective cohort studies in a general population. Thus, we examined this association in 133,014 participants in the Shanghai Women's and Men's Health Studies. Family history of liver cancer was categorized through dichotomous and proportional score approaches. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived using the Cox proportional hazards models with adjustment for potential confounders. A meta-analysis of observational studies through December 2013 on liver cancer risk in relation to family history of liver cancer was also performed. Study-specific risk estimates were combined using fixed or random effects models depending on whether significant heterogeneity was detected. For the Shanghai Women's and Men's Health Studies, 299 liver cancer cases were identified during follow-up through 2010. Family history of liver cancer was associated with liver cancer risk using both binary indicator (HR = 2.60, 95% CI: 1.77-3.80) and proportional score (high-risk vs. minimal-risk category: HR = 3.03, 95% CI: 1.73-5.31), with increasing HRs for increasing score categories. The meta-analysis also showed an increased risk for those with a family history of liver cancer (relative risk = 2.55, 95% CI: 2.05-3.16). Family history of liver cancer was related to increased risk of liver cancer in Chinese population. This risk is particularly high for those with an affected mother. The "dose-response" of risk with an increasing family history score of liver cancer might further facilitate future cancer prevention programs on identifying individuals with the highest potential liver cancer risk.
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Affiliation(s)
- Yang Yang
- State Key Laboratory of Oncogene and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Huang J, Zhang Y, Chen M, Huang J, Xu L, Chen M. Family history of hepatocellulcar carcinoma is not associated with its patients' prognosis after hepatectomy. World J Surg Oncol 2013; 11:280. [PMID: 24134117 PMCID: PMC3852743 DOI: 10.1186/1477-7819-11-280] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Accepted: 09/30/2013] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Family history of liver cancer is a major risk factor for hepatocellular carcinoma (HCC). In this study, we investigated the prognosis of patients with HCC with or without family history. METHODS Data for 1,313 patients who underwent hepatectomy as initial treatment for HCC between 2000 and 2008 at a tertiary cancer center hospital were retrieved from a prospective database. A positive family history was defined as a self-reported history of HCC in first-degree relatives. Clinicopathologic characteristics were compared by family history. Kaplan-Meier method and Cox proportional hazards regressions were applied for overall survival (OS) and disease-free survival (DFS). RESULTS Of 1,313 patients, 169 patients (12.9%) had first-degree relatives with a history of HCC. There were no significant differences between patients with or without family history in basic clinicopathologic characteristics. In either whole group or each stage according to the TNM staging system, first-degree family history was not associated with survival in all patients, hepatitis B virus-positive patients, as well as male patients. Multivariate analysis revealed that first-degree family history was not a prognostic factor, either for OS or DFS. CONCLUSION A first-degree family history of HCC is not associated with its patients' prognosis after hepatectomy.
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Affiliation(s)
| | | | | | | | | | - Minshan Chen
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, China.
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16
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Turati F, Edefonti V, Talamini R, Ferraroni M, Malvezzi M, Bravi F, Franceschi S, Montella M, Polesel J, Zucchetto A, La Vecchia C, Negri E, Decarli A. Family history of liver cancer and hepatocellular carcinoma. Hepatology 2012; 55:1416-25. [PMID: 22095619 DOI: 10.1002/hep.24794] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2011] [Accepted: 10/27/2011] [Indexed: 12/14/2022]
Abstract
UNLABELLED Familial clustering of hepatocellular carcinoma (HCC) has been frequently reported in eastern Asiatic countries, where hepatitis B infection is common. Little is known about the relationship between family history of liver cancer and HCC in Western populations. We carried out a case-control study in Italy, involving 229 HCC cases and 431 hospital controls. Data on family history were summarized through a binary indicator (yes/no) and a family history score (FHscore), considering selected family characteristics. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were obtained from unconditional multiple logistic regression models, including terms for age, sex, study center, education, tobacco smoking, alcohol drinking, hepatitis B surface antigen, and/or anti-hepatitis C virus positivity. We also performed a meta-analysis on family history of liver cancer and liver cancer updated to April 2011 using random-effects models. After adjustment for chronic infection with hepatitis B/C viruses, family history of liver cancer was associated with HCC risk, when using both the binary indicator (OR, 2.38; 95% CI, 1.01-5.58) and the FHscore, with increasing ORs for successive score categories. Compared to subjects without family history and no chronic infection with hepatitis B/C viruses, the OR for those exposed to both risk factors was 72.48 (95% CI, 21.92-239.73). In the meta-analysis, based on nine case-control and four cohort studies, for a total of approximately 3,600 liver cancer cases, the pooled relative risk for family history of liver cancer was 2.50 (95% CI, 2.06-3.03). CONCLUSION A family history of liver cancer increases HCC risk, independently of hepatitis. The combination of family history of liver cancer and hepatitis B/C serum markers is associated with an over 70-fold elevated HCC risk.
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Affiliation(s)
- Federica Turati
- Dipartimento di Epidemiologia, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
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17
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Zhang J, Xu F, Ouyang C. Joint effect of polymorphism in the N-acetyltransferase 2 gene and smoking on hepatocellular carcinoma. Tumour Biol 2012; 33:1059-63. [PMID: 22293947 DOI: 10.1007/s13277-012-0340-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2011] [Accepted: 01/19/2012] [Indexed: 12/22/2022] Open
Abstract
The N-acetyltransferase 2 gene (NAT2) has been implicated in the development of hepatocellular carcinoma (HCC). However, the results have been inconsistent. In this study, the authors performed a meta-analysis to clarify the association between NAT2 polymorphism and HCC risk. Published literatures from PubMed, EMBASE, CNKI, and Wan Fang Data were retrieved. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. Eight studies including 1,084 HCC cases and 1,682 controls were identified for the data analysis. The overall result showed that there was no statistically significant association between NAT2 genotypes and HCC risk (slow acetylation vs. rapid/intermediate acetylation: OR01.03, 95% CI 0.86–1.24). In the stratified analyses, NAT2 genotypes were also not significantly associated with HCC risk among both Europeans (OR01.11, 95% CI 0.86–1.43) and East Asians (OR01.01, 95% CI 0.65–1.56). Further subgroup analyses based on the smoking status showed that the effect size was statistically significant among the smokers (OR02.09, 95% CI 1.07–4.09), but not among those who never smoked (OR01.26, 95% CI 0.88–1.82). The present meta-analysis indicated that NAT2 genotypes were not associated with increased risk of HCC among the overall population but increased the risk of HCC among the smokers.
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Affiliation(s)
- Jie Zhang
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
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18
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Yang KC, Huang YS, Perng CL, Lin HC, Lee SD. Polymorphism of N-acetyltransferase 2 Gene and the Susceptibility to Alcoholic Liver Cirrhosis: Interaction With Smoking. Alcohol Clin Exp Res 2011; 35:1204-8. [DOI: 10.1111/j.1530-0277.2011.01453.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Metry KJ, Neale JR, Bendaly J, Smith NB, Pierce WM, Hein DW. Effect of N-acetyltransferase 2 polymorphism on tumor target tissue DNA adduct levels in rapid and slow acetylator congenic rats administered 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine or 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline. Drug Metab Dispos 2009; 37:2123-6. [PMID: 19666988 PMCID: PMC2774981 DOI: 10.1124/dmd.109.029512] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2009] [Accepted: 08/06/2009] [Indexed: 01/11/2023] Open
Abstract
2-Amino-3,8-dimethylimidazo-[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are suspected human carcinogens generated in well done meats. After N-hydroxylation, they are O-acetylated by N-acetyltransferase 2 (NAT2) to electrophiles that form DNA adducts. dG-C8-MeIQx and dG-C8-PhIP adducts have been identified in human tissues. In the female rat, administration of PhIP leads to mammary and colon tumors, whereas MeIQx induces liver tumors. Both humans and rats exhibit NAT2 genetic polymorphism yielding rapid and slow acetylator phenotypes. Because O-acetylation is an activation pathway, we hypothesized that MeIQx- and PhIP-induced DNA damage would be greater in tumor target tissues and higher in rapid than slow NAT2 acetylators. Adult female rapid and slow acetylator rats congenic at the Nat2 locus received a single dose of 25 mg/kg MeIQx or 50 mg/kg PhIP by gavage, and tissue DNA was isolated after 24 h. Deoxyribonucleoside adducts were identified and quantified by capillary liquid chromatography-tandem mass spectrometry using isotope dilution methods with deuterated internal standards. Major adducts were those bound to the C8 position of deoxyguanosine. dG-C8-PhIP DNA adducts were highest in colon, lowest in liver and did not significantly differ between rapid and slow acetylator congenic rats in any tissue tested. In contrast, dG-C8-MeIQx adducts were highest in liver and significantly (p < 0.001) higher in rapid acetylator liver than in slow acetylator liver. Our results are consistent with the tumor target specificity of PhIP and MeIQx and with increased susceptibility to MeIQx-induced liver tumors in rapid NAT2 acetylators.
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Affiliation(s)
- Kristin J. Metry
- Department of Pharmacology and Toxicology, James Graham Brown Cancer Center and Center for Environmental Genomics and Integrative Biology, University of Louisville School of Medicine, Louisville, Kentucky
| | - Jason R. Neale
- Department of Pharmacology and Toxicology, James Graham Brown Cancer Center and Center for Environmental Genomics and Integrative Biology, University of Louisville School of Medicine, Louisville, Kentucky
| | - Jean Bendaly
- Department of Pharmacology and Toxicology, James Graham Brown Cancer Center and Center for Environmental Genomics and Integrative Biology, University of Louisville School of Medicine, Louisville, Kentucky
| | - Ned B. Smith
- Department of Pharmacology and Toxicology, James Graham Brown Cancer Center and Center for Environmental Genomics and Integrative Biology, University of Louisville School of Medicine, Louisville, Kentucky
| | - William M. Pierce
- Department of Pharmacology and Toxicology, James Graham Brown Cancer Center and Center for Environmental Genomics and Integrative Biology, University of Louisville School of Medicine, Louisville, Kentucky
| | - David W. Hein
- Department of Pharmacology and Toxicology, James Graham Brown Cancer Center and Center for Environmental Genomics and Integrative Biology, University of Louisville School of Medicine, Louisville, Kentucky
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20
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Abstract
Arylamine N-acetyltransferases (NATs) are phase II xenobiotic metabolizing enzymes, catalyzing acetyl-CoA-dependent N- and O-acetylation reactions. All NATs have a conserved cysteine protease-like Cys-His-Asp catalytic triad inside their active site cleft. Other residues determine substrate specificity, while the C-terminus may control hydrolysis of acetyl-CoA during acetyltransfer. Prokaryotic NAT-like coding sequences are found in >30 bacterial genomes, including representatives of Actinobacteria, Firmicutes and Proteobacteria. Of special interest are the nat genes of TB-causing Mycobacteria, since their protein products inactivate the anti-tubercular drug isoniazid. Targeted inactivation of mycobacterial nat leads to impaired mycolic acid synthesis, cell wall damage and growth retardation. In eukaryotes, genes for NAT are found in the genomes of certain fungi and all examined vertebrates, with the exception of canids. Humans have two NAT isoenzymes, encoded by highly polymorphic genes on chromosome 8p22. Syntenic regions in rodent genomes harbour two Nat loci, which are functionally equivalent to the human NAT genes, as well as an adjacent third locus with no known function. Vertebrate genes for NAT invariably have a complex structure, with one or more non-coding exons located upstream of a single, intronless coding region. Ubiquitously expressed transcripts of human NAT1 and its orthologue, murine Nat2, are initiated from promoters with conserved Sp1 elements. However, in humans, additional tissue-specific NAT transcripts may be expressed from alternative promoters and subjected to differential splicing. Laboratory animals have been widely used as models to study the effects of NAT polymorphism. Recently generated knockout mice have normal phenotypes, suggesting no crucial endogenous role for NAT. However, these strains will be useful for understanding the involvement of NAT in carcinogenesis, an area extensively investigated by epidemiologists, often with ambiguous results.
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Affiliation(s)
- Sotiria Boukouvala
- Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.
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21
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Teixeira RLF, Miranda AB, Pacheco AG, Lopes MQP, Fonseca-Costa J, Rabahi MF, Melo HM, Kritski AL, Mello FCQ, Suffys PN, Santos AR. Genetic profile of the arylamine N-acetyltransferase 2 coding gene among individuals from two different regions of Brazil. Mutat Res 2007; 624:31-40. [PMID: 17509624 DOI: 10.1016/j.mrfmmm.2007.03.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2006] [Revised: 01/11/2007] [Accepted: 03/01/2007] [Indexed: 05/15/2023]
Abstract
Arylamine N-acetyltranferase 2 is the main enzyme responsible for the isoniazid metabolization into hepatotoxic intermediates and the degree of hepatotoxicity severity has been attributed to genetic variability in the NAT2 gene. The main goal of this study was to describe the genetic profile of the NAT2 gene in individuals from two different regions of Brazil: Rio de Janeiro and Goiás States. Therefore, after preparation of DNA samples from 404 individuals, genotyping of the coding region of NAT2 was performed by direct PCR sequencing. Thirteen previously described SNPs were detected in these Brazilian populations, from which seven: 191 G>A; 282 C>T; 341 T>C; 481 C>T; 590 G>A; 803 A>G and 857 G>A are the most frequent in other populations. The presence of so-called ethnic-specific SNPs in our population is in accordance with the Brazilians' multiple ancestry. Upon allele and genotype analysis, the most frequent NAT2 alleles were respectively NAT2*5B (33%), NAT2*6A (26%) and NAT2*4 (20%) being NAT2*5/*5 the more prevalent genotype (31.7%). These results clearly demonstrate the predominance in the studied Brazilian groups of NAT2 alleles associated with slow over the fast and intermediate acetylator genotypes. Additionally, in Rio de Janeiro, a significantly higher frequency of intermediate acetylation status was found when compared to Goiás (42.5% versus 25%) (p=0.05), demonstrating that different regions of a country with a population characterized by a multi-ethnic ancestry may present a large degree of variability in NAT2 allelic frequencies. This finding has implications in the determination of nationwide policies for use of appropriate anti-TB drugs.
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Affiliation(s)
- Raquel L F Teixeira
- Laboratory of Molecular Biology Applied to Mycobacteria, Department of Mycobacteriosis, IOC/Fiocruz, Avenida Brasil 4365, Manguinhos, Rio de Janeiro, CEP 21040-900, Brazil
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22
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Hernández A, Xamena N, Gutiérrez S, Velázquez A, Creus A, Surrallés J, Galofré P, Marcos R. Basal and induced micronucleus frequencies in human lymphocytes with different GST and NAT2 genetic backgrounds. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2006; 606:12-20. [PMID: 16621679 DOI: 10.1016/j.mrgentox.2006.02.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2005] [Revised: 01/20/2006] [Accepted: 02/22/2006] [Indexed: 10/24/2022]
Abstract
Basal and induced frequencies of genetic damage can be modulated by different host factors, including genes involved in phase II metabolism. Since polymorphic variants in the glutathione S-transferase (GST) and N-acetyl transferase (NAT) genes have been associated with cancer risk, we explored the possible links between GSTM1, GSTP1, GSTT1 and NAT2 variants and the frequency of micronuclei (MN) in human lymphocytes. This exploratory study was carried out in 30 thyroid cancer patients, before and after receiving an average dose of 109.9+/-1.3 mCi radioactive iodine as a co-adjuvant therapy. The results indicate that none of the polymorphisms studied show any kind of association with the basal level of micronuclei. When the same patients were followed after radioiodine exposure, a significant increase in the frequency of MN was observed in practically all of them (28/30), indicating the genotoxic activity of the ionising radiation exposure. The increase in MN frequency was not associated with any of the GST polymorphisms evaluated. Nevertheless, the presence of slow acetylator phenotypes and, in particular, the presence of the NAT2*7 allele was significantly associated with a lower increase of the MN frequency after radioiodine treatment.
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Affiliation(s)
- Alba Hernández
- Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, Spain
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23
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Kukongviriyapan V, Phromsopha N, Tassaneeyakul W, Kukongviriyapan U, Sripa B, Hahnvajanawong V, Bhudhisawasdi V. Inhibitory effects of polyphenolic compounds on human arylamine N-acetyltransferase 1 and 2. Xenobiotica 2006; 36:15-28. [PMID: 16507510 DOI: 10.1080/00498250500489901] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Arylamine N-acetyltransferases (NAT) are important enzymes involved in the metabolic activation of aromatic and heterocyclic amines and inhibitors of NAT enzymes may be valuable as chemopreventive agents. Phytochemicals including cinnamic acid derivatives, various classes of flavonoids and coumarins were tested for the inhibitory activity on NAT1 and NAT2 from human liver and the human cholangiocarcinoma cell line: KMBC cells. Assays were performed using p-aminobenzoic acid and sulfamethazine as selective substrates for NAT1 and NAT2, respectively. NAT1 and NAT2 activities were present in liver cytosol. However, the KMBC cells showed only NAT1 activity. There was a marked difference in the ability of the test chemicals to inhibit NAT1 and NAT2. Caffeic acid, ferulic acid, gallic acid and EGCG inhibited NAT1 but not NAT2, whereas scopuletin and curcumin inhibited NAT2 but not NAT1. Quercetin, kaemferol and other flavonoids, except epicatechin and silymarin, inhibited both enzymes. The kinetics of inhibition of NAT1 by caffeic acid, EGCG and quercetin were of the non-competitive type, whereas that of NAT2 by quercetin, curcumin and kaemferol was also of the non-competitive type. The most potent inhibitor was quercetin, which has the inhibitory constants for NAT1 and NAT2 of 48.6 +/- 17.3 and 10.0 +/- 1.8 microM, respectively.
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Affiliation(s)
- V Kukongviriyapan
- Department of Pharmacology, Faculty of Medicine, Liver Fluke & Cholangiocarcinoma Research Center, Khon Kaen, Thailand.
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24
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Machida H, Tsukamoto K, Wen CY, Shikuwa S, Isomoto H, Mizuta Y, Takeshima F, Murase K, Matsumoto N, Murata I, Kohno S, Wen CY. Crohn’s disease in Japanese is associated with a SNP-haplotype of N-acetyltransferase 2 gene. World J Gastroenterol 2005; 11:4833-7. [PMID: 16097053 PMCID: PMC4398731 DOI: 10.3748/wjg.v11.i31.4833] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [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 investigate the frequency and distribution of N-acetyltransferase 2 (NAT2) and uridine 5’-diphosphate (UDP)-glucuronosyltransferase 1A7 (UGT1A7) genes in patients with ulcerative colitis (UC) and Crohn’s disease (CD).
METHODS: Frequencies and distributions of NAT2 and UGT1A7 SNPs as well as their haplotypes were investigated in 95 patients with UC, 60 patients with CD, and 200 gender-matched, unrelated, healthy, control volunteers by PCR-restriction fragment length polymorphism (RFLP), PCR-denaturing high-performance liquid chromatography (DHPLC), and direct DNA sequencing.
RESULTS: Multiple logistic regression analysis revealed that the frequency of haplotype, NAT2*7B, significantly increased in CD patients, compared to that in controls (P = 0.0130, OR = 2.802, 95%CI = 1.243-6.316). However, there was no association between NAT2 haplotypes and UC, or between any UGT1A7 haplotypes and inflammatory bowel disease (IBD).
CONCLUSION: It is likely that the NAT2 gene is one of the determinants for CD in Japanese. Alternatively, a new CD determinant may exist in the 8p22 region, where NAT2 is located.
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Affiliation(s)
- Haruhisa Machida
- Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
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25
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Srivastava DSL, Mittal RD. Genetic polymorphism of the N-acetyltransferase 2 gene, and susceptibility to prostate cancer: a pilot study in north Indian population. BMC Urol 2005; 5:12. [PMID: 16083506 PMCID: PMC1190195 DOI: 10.1186/1471-2490-5-12] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2005] [Accepted: 08/06/2005] [Indexed: 01/14/2023] Open
Abstract
Background N-acetyltransferase 2 is phase II metabolizing enzyme that participates in the bioconversion of heterocyclic arylamines into electrophilic nitrenium ions, which are important ultimate carcinogens that are directly implicated in tumor initiation process. This study was conducted to examine; (1) whether the N-acetyltransferase 2 (NAT2) genotype is a risk factor for prostate cancer, (2) to study effect of NAT2 genotype on modifying prostate cancer risk from tobacco use. Methods The case control study was undertaken over a period of 28 months and included 130 prostate cancer patients (CaP) and 140 controls. The NAT2 genotypes were identified by PCR-RFLP method in DNA extracted from peripheral blood. Genotype frequencies and the association of genotypes with patients and control groups were assessed by logistic regression model. Results We observed non-significant association of rapid acetylator genotype NAT2 (OR = 1.452, 95% CI: 0.54–1.87, P = 0.136) in prostate cancer patients. However significant association was observed between rapid acetylator genotype NAT2 and CaP tobacco users (OR = 3.43, 95% CI: 1.68–7.02, P-value < 0.001) when compared with controls. Conclusion The data suggests that the NAT2 rapid acetylator genotypes may play an important role in determining the risk of developing prostate cancer particularly in the tobacco users of north Indian population.
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Affiliation(s)
- Daya SL Srivastava
- Department of Urology Sanjay Gandhi post Graduate Institute of Medical Sciences, Lucknow-226014, Uttar Pradesh, India
| | - Rama D Mittal
- Department of Urology Sanjay Gandhi post Graduate Institute of Medical Sciences, Lucknow-226014, Uttar Pradesh, India
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Radkevich LA, Korshunov IB, Pyn'ko NE, Morozova NV, Markarova EV, Nechaev DS, Piruzyan LA. The search for biochemical predictors of the NAT2 phenotype to optimize prophylaxis and pharmacotherapy of hepatic cirrhosis. DOKL BIOCHEM BIOPHYS 2005; 400:52-5. [PMID: 15846984 DOI: 10.1007/s10628-005-0031-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- L A Radkevich
- Center of Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, 119991 Russia
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Zhang XF, Bian JC, Zhang XY, Zhang ZM, Jiang F, Wang QM, Wang QJ, Cao YY, Tang BM. Are polymorphisms of N-acetyltransferase genes susceptible to primary liver cancer in Luoyang, China? World J Gastroenterol 2005; 11:1457-62. [PMID: 15770721 PMCID: PMC4305687 DOI: 10.3748/wjg.v11.i10.1457] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [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 identify whether the polymorphisms of the N-acetyltransferase (NAT) genes are susceptible to primary liver cancer (PLC) in Luoyang, a PLC low-incidence area of China.
METHODS: The NAT1 and NAT2 genotypes of 96 PLC cases and 173 controls were determined by PCR-RFLP. Both interaction between NAT1 or NAT2 and environmental risk factors were analyzed based on case control study.
RESULTS: Compared to the control group, the frequencies of alleles NAT1*3, NAT1*4, NAT1*10, NAT1*14B and alleles NAT2*4, NAT2*6, NAT2*7 in PLC group showed no statistically significant difference (χ2 = 2.61 and 4.16, respectively, both P>0.05). The frequencies of NAT1 genotypes NAT1*3/*3, NAT1*3/*4, NAT1*3/*10, NAT1*3/*14B, NAT1*4/*4, NAT1*4/*10, NAT1*4/*14B, NAT1*10/*10, NAT1*10/*14B, and NAT2 genotypes NAT2*4/*4, NAT2*4/*6, NAT2*4/*7, NAT2*6/*6, NAT2*6/*7 and NAT2*7/*7 also had no statistically significant difference between the two groups (χ2 = 11.86 and 2.94 respectively both, P>0.05). Neither the frequencies of rapid and slow NAT1 acetylators nor the frequencies of rapid and slow NAT2 acetylators were significantly different between the two groups (χ2 = 0.598 and 0.44, respectively, both P>0.05). The interaction between NAT1*10 and occupational exposures was found significant with an odds ratio of 3.40 (χ2 = 8.42, P = 0.004, OR 95%CI:1.03-11.22). But no interaction was found between NAT2 and any environmental risk factors.
CONCLUSION: The polymorphisms of NAT1 and NAT2 are not susceptible to PLC in Luoyang. Allele NAT1*10 interacts with occupational exposures.
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Affiliation(s)
- Xiu-Feng Zhang
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai 200032, China.
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Abstract
Hepatocellular carcinoma (HCC) is a major contributor to cancer incidence and mortality. There is a wide variation, however, in the global distribution of HCC. Eighty percent of the burden is borne by countries in Asia and sub-Saharan Africa. In most high-risk countries, principal risk factors include infection with hepatitis B virus and dietary exposure to aflatoxin B(1). In contrast, hepatitis C virus and alcohol consumption are more important risk factors in low-risk countries. In recent years, the incidence of HCC has decreased in some high-risk countries and increased in some low-risk countries. Reasons for both trends are not completely understood, but are likely related to public health efforts in Asia and the increase in hepatitis C virus infection in low-risk countries. Vaccination programs against hepatitis B virus will likely decrease the HCC rate even further in decades to come.
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Affiliation(s)
- Katherine A McGlynn
- HREB/DCEG, National Cancer Institute, EPS-7060, 6120 Executive Boulevard, Rockville, MD 20892, USA.
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29
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Piruzyan LA, Korshunov IB, Morozova NV, Pyn'ko NE, Radkevich LA. Prediction of chronic liver diseases on the basis of the N-acetyltransferase 2 phenotype. DOKL BIOCHEM BIOPHYS 2005; 395:84-7. [PMID: 15253558 DOI: 10.1023/b:dobi.0000025552.40172.db] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- L A Piruzyan
- Center of Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, ul. Kosygina 4, Moscow, 119991 Russia
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30
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Zhu ZZ, Cong WM, Liu SF, Dong H, Zhu GS, Wu MC. Homozygosity for Pro of p53 Arg72Pro as a potential risk factor for hepatocellular carcinoma in Chinese population. World J Gastroenterol 2005; 11:289-92. [PMID: 15633234 PMCID: PMC4205420 DOI: 10.3748/wjg.v11.i2.289] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [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: Codon 72 exon 4 polymorphism (Arg72Pro) of the p53 gene has been implicated in cancer risk. Our objective was to investigate the possible association between p53 Arg72Pro polymorphism and susceptibility to hepatocellular carcinoma (HCC) among Chinese population.
METHODS: The p53 Arg72Pro genotypes were determined by PCR-based restriction fragment length polymorphism (RFLP) analysis in 507 HCC cases and 541 controls. Odds ratios (ORs) for HCC and 95% confidence intervals (CIs) from unconditional logistic regression models were used to evaluate relative risks. Potential risk factors were included in the logistic regression models as covariates in the multivariate analyses on genotype and HCC.
RESULTS: The frequencies for Pro and Arg alleles were 44.5%, 55.5% in HCC cases, and 40.3% and 59.7% in controls, respectively. The Pro allele was significantly associated with the presence of HCC (P = 0.05) and had a higher risk for HCC (OR = 1.19, 95% CI 1.00-1.41) as compared with the Arg allele. After adjusted for potential risk factors, Arg/Pro heterozygotes had an 1.21-fold increased risk (95% CI 0.82-1.78, P = 0.34) of HCC compared with Arg homozygotes, whereas the risk for Pro homozygotes was 1.79 (95% CI 1.06-3.01, P = 0.03) times higher than that for Arg homozygotes. Pro-allele carriers had a higher relative risk of HCC than the Arg-only carriers (adjusted OR = 1.33, 95% CI 0.92-1.92, P = 0.13), although the difference was not statistically significant.
CONCLUSION: Homozygosity for Pro of p53 Arg72Pro is potentially one of the genetic risk factors for HCC in Chinese population. The p53 Arg72Pro polymorphism may be used as a stratification marker in screening individuals at a high risk of HCC.
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Affiliation(s)
- Zhong-Zheng Zhu
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
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31
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Gelatti U, Covolo L, Talamini R, Tagger A, Barbone F, Martelli C, Cremaschini F, Franceschi S, Ribero ML, Garte S, Nardi G, Donadon V, Donato F. N-Acetyltransferase-2, glutathione S-transferase M1 andT1 genetic polymorphisms, cigarette smoking and hepatocellular carcinoma: A case-control study. Int J Cancer 2005; 115:301-6. [PMID: 15688397 DOI: 10.1002/ijc.20895] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Our aim was to evaluate the role of N-acetyltransferase (NAT2) and glutathione S-transferase M1 and T1 (GSTM1 and GSTT1) polymorphisms in hepatocellular carcinoma (HCC) according to cigarette smoking, taking into account hepatitis B (HBV) and C (HCV) viral infection as well as alcohol consumption. A hospital-based case-control study was conducted in 2 areas of north Italy. Cases (n = 200) were patients hospitalized for HCC, and controls (n = 400) were patients admitted for reasons other than liver disease, neoplasms and tobacco- and alcohol-related diseases. Genotypes were determined using PCR and the PCR/restriction fragment length polymorphism-based method. The putative risk genotypes NAT2 slow acetylator, GSTM1 null and GSTT1 null were not associated with HCC (OR = 1.3, 95% CI 0.8-2.0; OR = 1.0, 95% CI 0.6-1.5; OR = 0.8, 95% CI 0.4-1.4, respectively). Although not statistically significant, an increase in HCC risk was observed among light smokers (1-20 pack-years) carrying GSTT1 null (OR = 1.7, 95% CI 0.6-4.7) and NAT2 slow acetylator (OR = 1.3, 95% CI 0.6-3.0) genotypes. In conclusion, there was no evidence for a gene-environment interaction in HCC risk for GSTM1, GSTT1 and NAT2 genotypes.
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Affiliation(s)
- Umberto Gelatti
- Institute of Hygiene, University of Brescia, Brescia, Italy.
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32
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Abstract
Nutritional genomics has tremendous potential to change the future of dietary guidelines and personal recommendations. Nutrigenetics will provide the basis for personalized dietary recommendations based on the individual's genetic make up. This approach has been used for decades for certain monogenic diseases; however, the challenge is to implement a similar concept for common multifactorial disorders and to develop tools to detect genetic predisposition and to prevent common disorders decades before their manifestation. The preliminary results involving gene-diet interactions for cardiovascular diseases and cancer are promising, but mostly inconclusive. Success in this area will require the integration of different disciplines and investigators working on large population studies designed to adequately investigate gene-environment interactions. Despite the current difficulties, preliminary evidence strongly suggests that the concept should work and that we will be able to harness the information contained in our genomes to achieve successful aging using behavioral changes; nutrition will be the cornerstone of this endeavor.
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Affiliation(s)
- Jose M Ordovas
- Nutrition and Genomics Laboratory, Jean Mayer-U.S. Department of Agriculture, Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA.
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