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Integrative genomics and pathway analysis identified prevalent FA-BRCA pathway alterations in arsenic-associated urinary bladder carcinoma: Chronic arsenic accumulation in cancer tissues hampers the FA-BRCA pathway. Genomics 2020; 112:5055-5065. [DOI: 10.1016/j.ygeno.2020.09.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 07/09/2020] [Accepted: 09/03/2020] [Indexed: 01/18/2023]
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Abstract
The 35th Annual Society of Toxicologic Pathology Symposium, held in June 2016 in San Diego, California, focused on "The Basis and Relevance of Variation in Toxicologic Responses." In order to review the basic tenants of toxicology, a "broad brush" interactive talk that gave an overview of the Cornerstones of Toxicology was presented. The presentation focused on the historical milestones and perspectives of toxicology and through many scientific graphs, data, and real-life examples covered the three basic principles of toxicology that can be summarized, as dose matters (as does timing), people differ, and things change (related to metabolism and biotransformation).
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Affiliation(s)
- A Wallace Hayes
- 1 Harvard University, Cambridge, Massachusetts, USA.,2 Michigan State University, East Lansing, Michigan, USA
| | - Darlene Dixon
- 3 National Institute of Environmental Health Sciences and the National Toxicology Program, National Institutes of Health (NIH), U.S. Department of Health and Human Services (HHS), Research Triangle Park, North Carolina, USA
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Zhu Z, Zhang J, Jiang W, Zhang X, Li Y, Xu X. Risks on N-acetyltransferase 2 and bladder cancer: a meta-analysis. Onco Targets Ther 2015; 8:3715-20. [PMID: 26715854 PMCID: PMC4685932 DOI: 10.2147/ott.s82927] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background It is known that bladder cancer disease is closely related to aromatic amine compounds, which could cause cancer by regulating of N-acetylation and N-acetyltransferase 1 and 2 (NAT1 and NAT2). The NAT2 slowed acetylation and would increase the risk of bladder cancer, with tobacco smoke being regarded as a risk factor for this increased risk. However, the relationship between NAT2 slow acetylation and bladder cancer is still debatable at present. This study aims to explore preliminarily correlation of NAT2 slow acetylation and the risk of bladder cancer. Methods The articles were searched from PubMed, Cochran, McGrane English databases, CBM, CNKI, and other databases. The extraction of bladder cancer patients and a control group related with the NAT2 gene were detected by the state, and the referenced articles and publications were also used for data retrieval. Using a random effects model, the model assumes that the studies included in the analysis cases belong to the overall population in the study of random sampling, and considering the variables within and between studies. Data were analyzed using STATA Version 6.0 software, using the META module. According to the inclusion and exclusion criteria of the literature study, 20 independent studies are included in this meta-analysis. Results The results showed that the individual differences of bladder cancer susceptibility might be part of the metabolism of carcinogens. Slow acetylation status of bladder cancer associated with the pooled odds ratio was 1.31 (95% confidence interval: 1.11–1.55). Conclusion The status of NAT2 slow N-acetylation is associated with bladder cancer risks, and may increase the risk of bladder cancer.
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Affiliation(s)
- Zongheng Zhu
- Department of General Surgery, Huangshi Love & Health Hospital, Huangshi, People's Republic of China
| | - Jinshan Zhang
- Department of Tumor surgery, Huangshi Central Hospital, Huangshi, People's Republic of China
| | - Wei Jiang
- Department of Urinary Surgery, Huangshi No 5 Hospital, Huangshi, People's Republic of China
| | - Xianjue Zhang
- Department of Urinary Surgery Jingzhou Central Hospital, Jingzhou, People's Republic of China
| | - Youkong Li
- Department of Urinary Surgery Jingzhou Central Hospital, Jingzhou, People's Republic of China
| | - Xiaoming Xu
- Department of Bone Surgery, Jingzhou Central Hospital, Jingzhou, People's Republic of China
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Inoue R, Isono M, Abe M, Abe T, Kobayashi H. A genotype of the polymorphic DNA repair gene MGMT is associated withde novoglioblastoma. Neurol Res 2013; 25:875-9. [PMID: 14669534 DOI: 10.1179/016164103771954005] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Glioblastoma is one of the most malignant tumors in humans. This tumor is thought to develop as a result of the accumulation of genetic abnormalities, mainly focused on the loss of heterozygosity on chromosome 10. O6-methylguanine-DNA methyltransferase (MGMT), which is one of the most important DNA repair proteins, has also been reported that enzymatic activity, as well as the methylation status of the promoter region of the MGMT gene, contributes to the therapeutic response of alkylating agents. We previously found three allelic variants in the MGMT gene and assayed the characteristics of these polymorphic proteins. We designed a case-control study to investigate the role of MGMT genotypic risk factors for primary brain tumors. We compared the distributions of MGMT genotypes in primary brain tumors and normal controls. The frequencies of MGMT genotypes in examined primary brain tumors were not different from normal subjects. However, the combined heterozygote of V1 and a wild allele (V1/W) was frequently detected in de novo glioblastoma group with significant difference. Interestingly, among glial tumors, the V1/W genotype was dominantly detected in the patients with de novo glioblastoma. This study suggests that the V1/W genotype of the MGMT gene may contribute to the de novo occurrence of glioblastoma.
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Affiliation(s)
- Ryo Inoue
- Department of Neurosurgery, Oita Medical University, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan.
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Singh N, Dubey S, Chinnaraj S, Golani A, Maitra A. Study of NAT2 Gene Polymorphisms in an Indian Population. Mol Diagn Ther 2012; 13:49-58. [DOI: 10.1007/bf03256314] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Baranska M, Trzcinski R, Dziki A, Rychlik-Sych M, Dudarewicz M, Skretkowicz J. The role of N-acetyltransferase 2 polymorphism in the etiopathogenesis of inflammatory bowel disease. Dig Dis Sci 2011; 56:2073-80. [PMID: 21321790 PMCID: PMC3112481 DOI: 10.1007/s10620-010-1527-4] [Citation(s) in RCA: 6] [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] [Received: 08/08/2010] [Accepted: 12/09/2010] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND PURPOSE Inflammatory bowel disease (IBD) consists of ulcerative colitis (UC) and Crohn's disease (CD), which are complex genetic disorders resulting from the interplay between several genetic and environmental risk factors. The arylamine N-acetyltransferase 2 (NAT2) enzyme detoxifies a wide spectrum of naturally occurring xenobiotics including carcinogens and drugs. Acetylation catalyzed by NAT2 is an important process in metabolic activation of arylamines to electrophilic intermediates that initiate carcinogenesis. The aim of our study was to determine whether there is any association between the susceptibility to inflammatory bowel disease among the variations of NAT2 genotypes. METHODS This study was carried out in 80 patients with IBD. The control group consisted of 100 healthy volunteers. The most common mutations found in the Caucasian population are at the positions 481T, 803G, 590A and 857A on the NAT2 gene. This was determined using the polymerase chain reaction-restriction fragment length polymorphism method with DNA extracted from peripheral blood. RESULTS Risk of IBD development was 3.86 for the carriers of the NAT2*5/NAT2*7 genotype and 2.53 for the carriers with NAT2*6/NAT2*7, but it was not statistically significant. A statistically significant correlation between the NAT2*7 allele prevalence and the risk for developing IBD was found (OR = 5.8; P = 0.005). CONCLUSIONS Higher prevalence of the NAT2*7 allele in patients with IBD and the obtained OR values could suggest that this mutation has the effect of increasing IBD development. Future studies are needed to confirm our assumptions on larger group of patients.
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Affiliation(s)
- M. Baranska
- Department of Pharmacogenetics, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland
| | - R. Trzcinski
- Department of General and Colorectal Surgery, Medical University of Lodz, Plac Hallera 1, 90-647 Lodz, Poland
| | - A. Dziki
- Department of General and Colorectal Surgery, Medical University of Lodz, Plac Hallera 1, 90-647 Lodz, Poland
| | - M. Rychlik-Sych
- Department of Pharmacogenetics, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland
| | - M. Dudarewicz
- Department of Pharmacogenetics, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland
| | - J. Skretkowicz
- Department of Pharmacogenetics, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland
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Walker K, Ginsberg G, Hattis D, Johns DO, Guyton KZ, Sonawane B. Genetic polymorphism in N-Acetyltransferase (NAT): Population distribution of NAT1 and NAT2 activity. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART B, CRITICAL REVIEWS 2009; 12:440-472. [PMID: 20183529 DOI: 10.1080/10937400903158383] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
N-Acetyltransferases (NAT) are key enzymes in the conjugation of certain drugs and other xenobiotics with an arylamine structure. Polymorphisms in NAT2 have long been recognized to modulate toxicity produced by the anti-tubercular drug isoniazid, with molecular epidemiologic studies suggesting a link between acetylator phenotype and increased risk for bladder cancer. Recent evidence indicates that the other major NAT isozyme, NAT1, is also polymorphic. The current analysis characterizes the main polymorphisms in both NAT2 and NAT1 in terms of their effect on enzyme activity and frequency in the population. Multiple NAT2 alleles (NAT2*5, *6, *7, and *14) have substantially decreased acetylation activity and are common in Caucasians and populations of African descent. In these groups, most individuals carry at least one copy of a slow acetylator allele, and less than 10% are homozygous for the wild type (fast acetylator) trait. Incorporation of these data into a Monte Carlo modeling framework led to a population distribution of NAT2 activity that was bimodal and associated with considerable variability in each population assessed. The ratio of the median to the first percentile of NAT2 activity ranged from 7 in Caucasians to 18 in the Chinese population. This variability indicates the need for more quantitative approaches (e.g., physiologically based pharmacokinetic [PBPK] modeling) to assess the full distribution of internal dose and adverse responses to aromatic amines and other NAT2 substrates. Polymorphisms in NAT1 are generally associated with relatively minor effects on acetylation function, with Monte Carlo analysis indicating less interindividual variability than seen in NAT2 analysis.
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Affiliation(s)
- Katy Walker
- Clark University, Center for Technology, Environment, and Development, Worcester, Massachusetts, USA
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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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Kozhekbaeva ZM, Glotov AS, Gra OA, Goldenkova-Pavlova IV, Bruskin SA, Agafonova EE, Markarova EV, Abdeev RM, Korsunskaya IM, Piruzyan AL, Barsky VE, Zasedatelev AS, Nasedkina TV. Analysis of NAT2 point mutations with biological microchips. Mol Biol 2007. [DOI: 10.1134/s0026893307040206] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Salanti G, Higgins JPT, White IR. Bayesian synthesis of epidemiological evidence with different combinations of exposure groups: application to a gene–gene–environment interaction. Stat Med 2006; 25:4147-63. [PMID: 16955540 DOI: 10.1002/sim.2689] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Meta-analysis to investigate the joint effect of multiple factors in the aetiology of a disease is of increasing importance in epidemiology. This task is often challenging in practice, because studies typically concentrate on studying the effect of only one exposure, sometimes may report the interaction between two exposures, but rarely address more complex interactions that involve more than two exposures. In this paper, we develop a meta-analysis framework that combines estimates from studies of multiple exposures. A key development is an approach to combining results from studies that report information on any subset or combination of the full set of exposures. The model requires assumptions to be made about the prevalence of the specific exposures. We discuss several possible model specifications and prior distributions, including information internal and external to the meta-analysis data set, and using fixed-effect and random-effects meta-analysis assumptions. The methodology is implemented in an original meta-analysis of studies relating the risk of bladder cancer to two N-acetyltransferase genes, NAT1 and NAT2, and smoking status.
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He LJ, Yu YM, Qiao F, Liu JS, Sun XF, Jiang LL. Genetic polymorphisms of N-acetyltransferase 2 and colorectal cancer risk. World J Gastroenterol 2005; 11:4268-71. [PMID: 16015704 PMCID: PMC4615457 DOI: 10.3748/wjg.v11.i27.4268] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [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: To identify the distribution of N-acetyltrasferase 2 (NAT2) polymorphism in Hebei Han Chinese and the effects of the polymorphism on the development of colorectal cancer.
METHODS: We performed a hospital-based case-control study of 237 healthy individuals and 83 colorectal cancer patients of Hebei Han Chinese. DNA was extracted from peripheral blood and cancer tissues. The genotypes of the polymorphisms were assessed by PCR-restriction fragment length polymorphism(RFLP).
RESULTS: There were four NAT2 alleles of WT, M1, M2, and M3 both in the healthy subjects and in the patients, and 10 genotypes of WT/WT, WT/M1, WT/M2, WT/M3, M1/M1, M1/M2, M1/M3, M2/M2, M2/M3, M3/M3. M2 allele was present in 15.61% of healthy subjects and 29.52% of patients (χ2 = 15.31, P < 0.0001), and M3 allele was present in 30.59% of healthy subjects and 16.87% of patients (χ2 = 25.33, P < 0.0001). There were more WT/M2 (χ2 = 34.42, P < 0.0001, odd ratio = 4.99, 95%CI = 2.27-9.38) and less WT/M3 (χ2 = 3.80, P = 0.03) in the patients than in the healthy subjects. In 70.3% of the patients, there was a difference in NAT2 genotype between their tumors and blood cells. Patients had more WT/M2 (χ2 = 5.11, P = 0.02) and less M2/M3 (χ2 = 4.27, P = 0.039) in their blood cells than in the tumors. Furthermore, 53.8% (7/13) of M2/M3 in tumors were from WT/M2 of blood cells.
CONCLUSION: There is a possible relationship between the NAT2 polymorphisms and colorectal cancer in Hebei Han Chinese. The genotype WT/M2 may be a risk factor for colorectal cancer.
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Affiliation(s)
- Lu-Jun He
- Department of Biochemistry, Hebei Medical University, Shijiazhuang 050017, Hebei Province, China
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Schnakenberg E, Lustig M, Breuer R, Werdin R, Hübotter R, Dreikorn K, Schloot W. Gender-specific effects of NAT2 and GSTM1 in bladder cancer. Clin Genet 2000; 57:270-7. [PMID: 10845567 DOI: 10.1034/j.1399-0004.2000.570405.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
One approach for risk assessment of cancer is the evaluation of polymorphic enzymes involved in cancer using molecular tools. Phase II enzymes are involved in the detoxification of several drugs, environmental substances and carcinogenic compounds. Here, we analyzed enzymes for their putative relevance in urinary bladder cancer. The hereditable enzyme polymorphism of arylamine N-acetyltransferase 2 (NAT2) and glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) was studied in 157 hospital-based patients and in 223 control subjects. Slow acetylation was not observed to be a significant risk factor of developing bladder cancer (OR: 1.33; 95% CI 0.85-2.09). One genotype responsible for slow acetylation (NAT2*5B/*6A) was observed significantly more frequently in bladder cancer patients compared with control subjects (OR: 1.63; 95% CI 1.03-2.58). Gender-specific effects were observed when patients were divided into subgroups. In male patients, slow acetylators were identified as carrying a significant increased risk of developing bladder cancer, in particular when the genotype NAT2*5B/*6A was combined with the GSTM1 null genotype (OR: 4.39; 95% CI 1.98-9.74). By contrast, the same genotype combination significantly protected female patients from bladder cancer (OR: 0.21; 95% CI 0.06-0.80).
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Affiliation(s)
- E Schnakenberg
- Center for Human Genetics and Genetic Counselling, University of Bremen, Germany
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Johns LE, Houlston RS. N-acetyl transferase-2 and bladder cancer risk: a meta-analysis. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2000; 36:221-227. [PMID: 11044903 DOI: 10.1002/1098-2280(2000)36:3<221::aid-em5>3.0.co;2-q] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
Interindividual differences in bladder cancer susceptibility may be partly mediated through polymorphic variability in the metabolism of carcinogens. N-acetyl transferase-2 (NAT2) has been extensively studied as a risk factor in this context, but the results are inconsistent. In some studies the failure to demonstrate a relationship may be a consequence of a lack of statistical power. To overcome lack of power, data from 21 published case-control studies were pooled in a meta-analysis using a random-effects model. The pooled odds ratio of bladder cancer associated with slow acetylator status was 1.31 (95% CI: 1.11-1.55). The results suggest that NAT2 slow acetylator status is associated with a modest increase in risk of bladder cancer. There was, however, heterogeneity between studies. It is clear from this overview that greater attention should be paid to the design of these types of study.
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Affiliation(s)
- L E Johns
- Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, United Kingdom
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