Pharmacogenetics of the arylamine N-acetyltransferases

Butcher, Neville J.; Boukouvala, Sotiria; Sim, Edith; Minchin, Rodney F.

doi:10.1038/sj.tpj.6500053

Cited by 168 publications

(133 citation statements)

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“…Both of the human isoforms, NAT1 and NAT2, display interindividual variations and associations between NAT genotypes, and cancer risk has been established (1,3,5). In addition, these cytosolic enzymes are encoded by two separate genes located on 8p22, a chromosomal region commonly deleted in certain human cancers (5)(6)(7). This raised the possibility that the absence of NATs or their inactivation may contribute to carcinogenesis and/or tumor progression (6,8,9).…”

Section: From the ‡Cnrs-unité Mixte De Recherche 7000 Faculté De Médmentioning

confidence: 99%

“…In humans, these reactions are catalyzed by two xenobiotic-metabolizing enzymes (XME), 1 arylamine N-acetyltransferase 1 and arylamine N-acetyltransferase 2 (NAT1 and NAT2; EC 2.3.1.5). Both of the human isoforms, NAT1 and NAT2, display interindividual variations and associations between NAT genotypes, and cancer risk has been established (1,3,5). In addition, these cytosolic enzymes are encoded by two separate genes located on 8p22, a chromosomal region commonly deleted in certain human cancers (5)(6)(7).…”

Section: From the ‡Cnrs-unité Mixte De Recherche 7000 Faculté De Médmentioning

confidence: 99%

“…Many arylamines, such as 4-aminobiphenyl (a tobacco-associated compound) and benzidine (occupational exposure) are important environmental carcinogens (1)(2)(3), and their biotransformation through N-and/or O-acetylation has been linked to carcinogenesis (2)(3)(4)(5). In humans, these reactions are catalyzed by two xenobiotic-metabolizing enzymes (XME), 1 arylamine N-acetyltransferase 1 and arylamine N-acetyltransferase 2 (NAT1 and NAT2; EC 2.3.1.5).…”

Section: From the ‡Cnrs-unité Mixte De Recherche 7000 Faculté De Médmentioning

confidence: 99%

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Peroxynitrite Irreversibly Inactivates the Human Xenobioticmetabolizing Enzyme Arylamine N-Acetyltransferase 1 (NAT1) in Human Breast Cancer Cells

Dairou

Atmane

Rodrigues‐Lima

et al. 2004

Journal of Biological Chemistry

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Arylamine N-acetyltransferases (NATs) play an important role in the detoxification and metabolic activation of a variety of aromatic xenobiotics, including numerous carcinogens. Both of the human isoforms, NAT1 and NAT2, display interindividual variations, and associations between NAT genotypes and cancer risk have been established. Contrary to NAT2, NAT1 has a ubiquitous tissue distribution and has been shown to be expressed in cancer cells. Given that the activity of NAT1 depends on a reactive cysteine that can be a target for oxidants, we studied whether peroxynitrite, a highly reactive nitrogen species involved in human carcinogenesis, could inhibit the activity of endogenous NAT1 in MCF7 breast cancer cells. We show here that exposure of MCF7 cells to physiological concentrations of peroxynitrite and to a peroxynitrite generator (3-morpholinosydnonimine Nethylcarbamide, or SIN1) leads to the irreversible inactivation of NAT1 in cells. Further kinetic and mechanistic analyses using recombinant NAT1 showed that the enzyme is rapidly (k inact ‫؍‬ 5 ؋ 10 4 M ؊1 ⅐s ؊1 ) and irreversibly inactivated by peroxynitrite. This inactivation is due to oxidative modification of the catalytic cysteine. We conclude that the reducing cellular environment of MCF7 cells does not sufficiently protect NAT1 from peroxynitrite-dependent inactivation and that only high concentrations of reduced glutathione could significantly protect NAT1. Thus, cellular generation of peroxynitrite may contribute to carcinogenesis and tumor progression by weakening key cellular defense enzymes such as NAT1.

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Section: From the ‡Cnrs-unité Mixte De Recherche 7000 Faculté De Médmentioning

confidence: 99%

Section: From the ‡Cnrs-unité Mixte De Recherche 7000 Faculté De Médmentioning

confidence: 99%

Section: From the ‡Cnrs-unité Mixte De Recherche 7000 Faculté De Médmentioning

confidence: 99%

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Peroxynitrite Irreversibly Inactivates the Human Xenobioticmetabolizing Enzyme Arylamine N-Acetyltransferase 1 (NAT1) in Human Breast Cancer Cells

Dairou

Atmane

Rodrigues‐Lima

et al. 2004

Journal of Biological Chemistry

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“…This polymorphism arises from variations in DNA sequence resulting in the production of NAT2 proteins with variable enzyme activity or stability. 5 The impact of different acetylation activities of NAT2 enzyme on cancer susceptibility varies among different organs. O-acetylation by rapid NAT2 enzyme increased the risk of colon cancer, probably owing to extensive activities of heterocyclic amines (such as 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine, i.e., PhIP).…”

mentioning

confidence: 99%

Polymorphisms at XPD and XRCC1 DNA repair loci and increased risk of oral leukoplakia and cancer among NAT2 slow acetylators

Majumder

Sikdar

Ghosh

et al. 2007

Intl Journal of Cancer

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Polymorphisms at N-acetyl transferase 2 locus (NAT2) lead to slow, intermediate and rapid acetylation properties of the enzyme. Improper acetylation of heterocyclic and aromatic amines, present in tobacco, might cause DNA adduct formation. Generally, DNA repair enzymes remove these adduct to escape malignancy. But, tobacco users carrying susceptible NAT2 and DNA repair loci might be at risk of oral leukoplakia and cancer. In this study, 389 controls, 224 leukoplakia and 310 cancer patients were genotyped at 5 polymorphic sites on NAT2 and 3 polymorphic sites on each of XRCC1 and XPD loci by PCR-RFLP method to determine the risk of the diseases. None of the SNPs on these loci independently could modify the risk of the diseases in overall population but variant genotype (Gln/Gln) at codon 399 on XRCC1 and major genotype (Lys/Lys) at codon 751 on XPD were associated with increased risk of leukoplakia and cancer among slow acetylators, respectively (OR 5 4.2, 95% CI 5 1.2-15.0; OR 5 1.6, 95% CI 5 1.1-2.3, respectively). Variant genotype (Asn/Asn) at codon 312 on XPD was also associated with increased risk of cancer among rapid and intermediate acetylators (OR 5 1.9, 95% CI 5 1.2-2.9). Variant C-G-A haplotype at XRCC1 was associated with increased risk of leukoplakia (OR 5 1.7, 95% CI 5 1.2-2.4) but leukoplakia and cancer in mixed tobacco users (OR 5 3.1, 95% CI 5 1.4-7.1, OR 5 2.4, 95% CI 5 1.1-5.4, respectively) among slow acetylators. Although none of the 3 loci could modulate the risk of the diseases independently but 2 loci in combination, working in 2 different biochemical pathways, could do so in these patient populations. ' 2007 Wiley-Liss, Inc.Key words: tobacco use; oral cancer; leukoplakia, NAT2; XPD; XRCC1; polymorphism As an early sign of damage to oral mucosa, tobacco smokers and chewers often develop different precancerous lesions, such as leukoplakia, erythroplakia, submucous fibrosis, etc., and these lesions are easily accessible to diagnosis. Annual incidence of oral leukoplakia has been reported as 0.2-11.7% in different populations of India 1-3 and about 2-12% of leukoplakia becomes malignant within several years. 2 Since leukoplakia is one of the good predictors of oral cancer so diagnosis and treatment of leukoplakia will be a useful strategy to control oral cancer incidence. Annually about 270,000 cases of oral cancer are reported worldwide but about 82,000 of them are diagnosed in India. 4 Major procarcinogens present in the tobacco smoke are polycyclic aromatic hydrocarbons, aromatic and heterocyclic amines and nitroso-compounds whereas nitrosamines and aromatic and heterocyclic amines are major components present in smokeless tobacco. Most of the tobacco carcinogens generally undergo bioactivation and inactivation by phase I and phase II enzymes respectively. Human N-acetylation transferase 2 (NAT2) is one of the phase II enzymes that participate in the bioconversion of aromatic and heterocyclic amines and variation in NAT2 enzyme activity is defined as polymorphism in N-acetylation capacit...

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“…Mutation in one to a combination of four SNPs has been correlated with the slow, intermediate, and rapid acetylation phenotypes (Butcher et al, 2002). However in this study, we just focused on the investigation of the main disease predisposing SNPs, G to A transition at 5'-UTR position 61 of the EGF gene and of the NAT2 SNP at position 857.…”

Section: Introductionmentioning

confidence: 99%

Genetic polymorphisms of EGF 5'-UTR and NAT2 857G/A associated with glioma in a case control study of Malaysian patients

Muthusamy

Lian²,

Vairavan³

et al. 2012

Genet. Mol. Res.

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ABSTRACT. Studies of genetic mutations that have been used in predicting glioma prognosis have revealed a complex relationship between clinical and genetic factors. Epidermal growth factor (EGF) and the NAT2 gene play a central role in carcinogenesis. An adenine (A) to guanine (G) single nucleotide polymorphism at position 61 in the 5'-untranslated region (5'-UTR) of the EGF gene has been found to be associated with levels of EGF production, and the mutations in the NAT2 gene have been postulated as a risk factor for cancer. We investigated EGF and the NAT2 gene in 13 glioma tissue samples and 12 normal controls. In the EGF 5'-UTR 61G polymorphism, the heterozygote GA was the most common genotype in the glioma patients. In the NAT2 polymorphism at nucleotide position 857G/A, the G allele and the GG genotype were the most prevalent forms in both the glioma and normal samples. We did not find any homozygous AA genotypes in the glioma patients. Based on this preliminary evidence, the EGF 5'-UTR at position 61 and the NAT2 SNP at position 857 polymorphisms are associated with increased risk for glioma.

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Pharmacogenetics of the arylamine N-acetyltransferases

Cited by 168 publications

References 113 publications

Peroxynitrite Irreversibly Inactivates the Human Xenobioticmetabolizing Enzyme Arylamine N-Acetyltransferase 1 (NAT1) in Human Breast Cancer Cells

Peroxynitrite Irreversibly Inactivates the Human Xenobioticmetabolizing Enzyme Arylamine N-Acetyltransferase 1 (NAT1) in Human Breast Cancer Cells

Polymorphisms at XPD and XRCC1 DNA repair loci and increased risk of oral leukoplakia and cancer among NAT2 slow acetylators

Genetic polymorphisms of EGF 5'-UTR and NAT2 857G/A associated with glioma in a case control study of Malaysian patients

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