Correlation between N-acetyltransferase activity and NAT2 genotype in Chinese male

Rothman, Nathaniel; Hayes, Richard B.; Bi, Wenfang; Caporaso, Neil E.; Broly, F.; Woosley, Raymond L.; Yin, Shu; Feng, Peng; You, Xiejun; Meyer, Urs

doi:10.1097/00008571-199310000-00004

Cited by 45 publications

(20 citation statements)

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“…A case-control study of surviving bladder cancer cases from the cohort (17) showed that neither the slow NAT2 phenotype nor genotype was associated with an increased risk of bladder cancer (odds ratio for slow phenotype = 0.3; 95% confidence interval = 0.1-1.3). In addition, all NAT2 alleles identified in this population had been previously detected in Caucasians and similarly correlated with NAT2 phenotype (18). These results suggest that N-acetylation by NAT2 is not a key detoxifying pathway for BZ.…”

supporting

confidence: 74%

The impact of interindividual variation in NAT2 activity on benzidine urinary metabolites and urothelial DNA adducts in exposed workers.

Rothman

Bhatnagar

Hayes

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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Several epidemiologic studies indicate that NAT2-related slow N-acetylation increases bladder cancer risk among workers exposed to aromatic amines, presumably because N-acetylation is important for the detoxification of these compounds. Previously, we showed that NAT2 polymorphisms did not influence bladder cancer risk among Chinese workers exposed exclusively to benzidine (BZ), suggesting that NAT2 N-acetylation is not a critical detoxifying pathway for this aromatic amine. To evaluate the biologic plausibility of this finding, we carried out a cross-sectional study of 33 workers exposed to BZ and 15 unexposed controls in Ahmedabad, India, to evaluate the presence of BZ-related DNA adducts in exfoliated urothelial cells, the excretion pattern of BZ metabolites, and the impact of NAT2 activity on these outcomes. Four DNA adducts were significantly elevated in exposed workers compared to controls; of these, the predominant adduct cochromatographed with a synthetic N-(3'-phosphodeoxyguanosin-8-yl)-N'-acetylbenzidine standard and was the only adduct that was significantly associated with total BZ urinary metabolites (r = 0.68, P < 0.0001). To our knowledge this is the first report to show that BZ forms DNA adducts in exfoliated urothelial cells of exposed humans and that the predominant adduct formed is N-acetylated, supporting the concept that monofunctional acetylation is an activation, rather than a detoxification, step for BZ. However, because almost all BZ-related metabolites measured in the urine of exposed workers were acetylated among slow, as well as rapid, acetylators (mean ± SD 95 ± 1.9o vs. 97 + 1.6%, respectively) and NAT2 activity did not affect the levels of any DNA adduct measured, it is unlikely that interindividual variation in NAT2 function is relevant for BZ-associated bladder carcinogenesis.Aromatic amines must be metabolized within the host in order to exert mutagenic or carcinogenic activity (1). For many aromatic monoamines, including those found in tobacco smoke such as 4-aminobiphenyl (4-ABP) and 2-naphthylamine, N-acetylation appears to be a detoxification pathway, with the acetylated metabolite being excreted into the urine before it can be N-oxidized to a reactive form (2). In contrast, acetylation may be an activation pathway for benzidine (BZ), an aromatic diamine, in that N-acetylation of one amine group has been shown to facilitate N-oxidation to a reactive species by cytochrome P-450 (3, 4). Alternatively, BZ may be directly activated by prostaglandin-H synthetase in the bladder to benzidinediimine (the two-electron oxidation product), which can bind to DNA (5, 6). Thus, for BZ, the impact of acetylation on the production of the critical activated metabolite(s) is less certain and may be more complicated than for aromatic monoamines.The capacity to N-acetylate is polymorphic in humans (2); slow acetylators are homozygotic for a mutated N-acetyltransferase gene (NA72) that is generally responsible for decreased activity (7,8). In 1979, Lower et al. (9) proposed that individu...

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supporting

confidence: 74%

The impact of interindividual variation in NAT2 activity on benzidine urinary metabolites and urothelial DNA adducts in exposed workers.

Rothman

Bhatnagar

Hayes

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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“…Notably, Arab populations consist of 81.6% slow acetylators, with a predominantly NAT2 * 5/ * 5 genotype (37). These data (including our results) differ enormously from those of other populations in which the proportion of slow acetylators is low, such as Chinese, Korean, and Central American Indians (20,33,(38)(39)(40)(41).…”

Section: Discussioncontrasting

confidence: 94%

Genotype and phenotype of NAT2 and the occurrence of adverse drug reactions in Mexican individuals to an isoniazid-based prophylactic chemotherapy for tuberculosis

Bravo¹

2008

Mol Med Rep

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Abstract. Isoniazid (INH) is a drug extensively used as a prophylactic and therapeutic agent for human tuberculosis (TB). INH is metabolized by the enzymatic activity of N-acetyltransferase 2 (NAT2). Human NAT2, encoded by a highly polymorphic gene, is involved in the biotransformation of xenobiotics, including drugs and certain chemical carcinogens. Numerous studies have established the correlation between the acetylator phenotype and the NAT2 genotype in several populations; however, little is known regarding LatinAmerican populations and the pharmacogenetics of NAT2. Here, we report the molecular genotyping of the NAT2 gene, the acetylator phenotype, and the incidence of INH-related adverse reactions in a group of 25 Mexican individuals enrolled in a prophylactic protocol for TB. Using both the NAT2 genotyping and acetylation phenotyping approach, we found a ratio of 69.2 and 30.8% of slow and fast acetylators, respectively. Concordance of the NAT2 genotype and phenotype classification was 88% in the bimodal model. Regarding INH-related adverse reactions, only 2 individuals (8%) exhibited declared gastric intolerance. In our study group, we found an association between the NAT2 genotype and acetylator phenotype (OR=7.78, 95% CI, 0.87-87.98, Fisher's exact test, p<0.05), but did not find any genotype or phenotype association with the incidence of INH-related adverse reactions (Fisher's exact test, p>0.05).

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“…51,52 Finally, the correlation between NAT2 genotype and NAT2 phenotype measured by different probes is the same among Chinese and Caucasian populations. [53][54][55] Therefore, it is unlikely that an ethnic difference could explain these results, as there are no equivalent, welldesigned studies conducted in Caucasian populations exposed exclusively to benzidine.…”

Section: Discussionmentioning

confidence: 99%

NAT2 slow acetylation and bladder cancer in workers exposed to benzidine

Carreón

Ruder

Schulte

et al. 2005

Intl Journal of Cancer

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This study expands a previous study of NAT2 polymorphisms and bladder cancer in male subjects occupationally exposed only to benzidine. The combined analysis of 68 cases and 107 controls from a cohort of production workers in China exposed to benzidine included 30 new cases and 67 controls not previously studied. NAT2 enzymatic activity phenotype was characterized by measuring urinary caffeine metabolite ratios. PCR-based methods identified genotypes for NAT2, NAT1 and GSTM1. NAT2 phenotype and genotype data were consistent. A protective association was observed for the slow NAT2 genotype (bladder cancer OR = 0.3; 95% CI = 0.1 = 1.0) after adjustment for cumulative benzidine exposure and lifetime smoking. Individuals carrying NAT1wt/*10 and NAT1*10/*10 showed higher relative risks of bladder cancer (OR = 2.8, 95% CI = 0.8-10.1 and OR = 2.2, 95% CI = 0.6-8.3, respectively). No association was found between GSTM1 null and bladder cancer. A metaanalysis risk estimate of case-control studies of NAT2 acetylation and bladder cancer in Asian populations without occupational arylamine exposures showed an increased risk for slow acetylators. The lower limit of the confidence interval (OR = 1.4; 95% CI = 1.0-2.0) approximated the upper confidence interval for the estimate obtained in our analysis. These results support the earlier finding of a protective association between slow acetylation and bladder cancer in benzidine-exposed workers, in contrast to its established link as a risk factor for bladder cancer in people exposed to 2-naphthylamine and 4-aminobiphenyl. Study findings suggest the existence of key differences in the metabolism of mono- and diarylamines.

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Correlation between N-acetyltransferase activity and NAT2 genotype in Chinese male

Cited by 45 publications

References 0 publications

The impact of interindividual variation in NAT2 activity on benzidine urinary metabolites and urothelial DNA adducts in exposed workers.

The impact of interindividual variation in NAT2 activity on benzidine urinary metabolites and urothelial DNA adducts in exposed workers.

Genotype and phenotype of NAT2 and the occurrence of adverse drug reactions in Mexican individuals to an isoniazid-based prophylactic chemotherapy for tuberculosis

NAT2 slow acetylation and bladder cancer in workers exposed to benzidine

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