Molecular genetics of human polymorphic N-acetyltransferase: enzymatic analysis of 15 recombinant wild-type, mutant, and chimeric NAT2 allozymes

Heln, David W.; Ferguson, R. James; Doll, Mark A.; Rustan, Timothy D.; Gray, Kevin A.

doi:10.1093/hmg/3.5.729

Cited by 104 publications

(89 citation statements)

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“…NAT2 allozymes encoded by alleles with base substitutions at positions 191, 590, or 857 were found to be significantly more unstable in bacterial expression systems than the wild-type protein. 52,61,64 However, in these studies the amount of immunodetectable NAT2 protein was not different upon expression of the variant and wild-type alleles. This is in contrast to the earlier observations by Grant and coworkers 57 who showed that liver NAT2 content was markedly reduced in slow acetylators, suggesting that the artificial environment of bacterial expression systems may not accurately reflect what occurs in mammalian cells with regard to protein degradation.…”

Section: Human Natsmentioning

confidence: 56%

Pharmacogenetics of the arylamine N-acetyltransferases

et al. 2002

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The arylamine N-acetyltransferases (NATs) are involved in the metabolism of a variety of different compounds that we are exposed to on a daily basis. Many drugs and chemicals found in the environment, such as those in cigarette smoke, car exhaust fumes and in foodstuffs, can be either detoxified by NATs and eliminated from the body or bioactivated to metabolites that have the potential to cause toxicity and/or cancer. NATs have been implicated in some adverse drug reactions and as risk factors for several different types of cancers. As a result, the levels of NATs in the body have important consequences with regard to an individual's susceptibility to certain druginduced toxicities and cancers. This review focuses on recent advances in the molecular genetics of the human NATs.

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Section: Human Natsmentioning

confidence: 56%

Pharmacogenetics of the arylamine N-acetyltransferases

et al. 2002

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“…NAT2-dependent N-acetylation ( Figure 1) and O-acetylation ( Figure 4) have been reported in urinary bladder cytosol from rapid and slow acetylator Syrian hamsters congenic at the NAT2 locus. As both NAT1 and NAT2 catalyse the metabolism of aromatic amine carcinogens (Minchin et al, 1992;Hein et al, 1993bHein et al, , 1994bHein et al, , 1995, genetic polymorphism in NAT1 and/or NAT2 may modify cancer risk related to exposures to these carcinogens.…”

Section: Phenotypic Expression Of the Nat2 Polymorphismmentioning

confidence: 99%

“…These two SNPs and identification of NAT2*12 and NAT2*13 alleles often are not determined in epidemiological studies as they are considered rare. However, as shown in Figure 5, their frequency is not rare in many ethnic groups and it is important both to assess their frequency and to correctly assign them as rapid or slow (Hein et al, 1994bFretland et al, 2001;Zang et al, 2005). Three studies using caffeine as a phenotype probe suggested that NAT2*12 and NAT2*13 were associated with slow acetylation phenotype (Cascorbi et al, 1995;Gross et al, 1999;Bolt et al, 2005).…”

Section: Molecular Basis For Altered Function Of Nat2 Polymorphic Varmentioning

confidence: 99%

“…The latter study (Parkin et al, 1997) included five subjects possessing the NAT2*13 allele and 20 subjects possessing the NAT2*12A allele that consistently confirmed rapid acetylator status based upon measured phenotypes in several people. Recombinant NAT2 proteins differ in heat stability (Ferguson et al, 1994;Hein et al, 1994b;Grant et al, 1997;Leff et al, 1999;Fretland et al, 2001). The NAT2 7B allozyme has altered affinity for some but not other substrates (Hein et al, 1994b;Hickman et al, 1995), suggesting that the expression of acetylator phenotype is dependent upon the substrate.…”

Section: Molecular Basis For Altered Function Of Nat2 Polymorphic Varmentioning

confidence: 99%

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N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk

2006

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A role for the N-acetyltransferase 2 (NAT2) genetic polymorphism in cancer risk has been the subject of numerous studies. Although comprehensive reviews of the NAT2 acetylation polymorphism have been published elsewhere, the objective of this paper is to briefly highlight some important features of the NAT2 acetylation polymorphism that are not universally accepted to better understand the role of NAT2 polymorphism in carcinogenic risk assessment. NAT2 slow acetylator phenotype(s) infer a consistent and robust increase in urinary bladder cancer risk following exposures to aromatic amine carcinogens. However, identification of specific carcinogens is important as the effect of NAT2 polymorphism on urinary bladder cancer differs dramatically between monoarylamines and diarylamines. Misclassifications of carcinogen exposure and NAT2 genotype/phenotype confound evidence for a real biological effect. Functional understanding of the effects of NAT2 genetic polymorphisms on metabolism and genotoxicity, tissue-specific expression and the elucidation of the molecular mechanisms responsible are critical for the interpretation of previous and future human molecular epidemiology investigations into the role of NAT2 polymorphism on cancer risk. Although associations have been reported for various cancers, this paper focuses on urinary bladder cancer, a cancer in which a role for NAT2 polymorphism was first proposed and for which evidence is accumulating that the effect is biologically significant with important public health implications.

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“…After activation, HA are either detoxified or activated to more potent carcinogens by N-acetyltransferases (NAT1 and NAT2) [11]. Several polymorphisms are known in the NAT1 and NAT2 genes, which result phenotypically in individuals who are slow or rapid acetylators [12].…”

Section: Introductionmentioning

confidence: 99%

GSTM1 Null Genotype, Red Meat Consumption and Breast Cancer Risk (The Netherlands)

Hel

Peeters

Hein

et al. 2004

Cancer Causes Control

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Objective: We studied whether polymorphisms in N-acetyltransferase 1 and 2 and Glutathione S-transferase M1 and T1 genes modify the association between meat consumption and breast cancer. Methods: A nested case control was conducted in a Dutch prospective cohort. Breast cancer cases (229) and controls (264) were frequency matched on age, town and menopausal status. Results: There is no relation between any type of meat consumption (i.e., total meat, processed meat, fresh meat, red meat and white meat) and breast cancer risk. Neither presence of NAT1 or NAT2 rapid genotype, or GSTT1 null genotype, alone or in combination with meat consumption affects breast cancer risk. Absence of GSTM1 shows 46% increased breast cancer risk (OR ¼ 1.46 (95% confidence interval, 95% CI ¼ 1.02-2.09)). When stratifying according to combined 'GSTM1 genotype-meat consumption' categories, breast cancer risk is slightly increased with consumption of red meat both in women with genotype GSTM1 presence (OR ¼ 1.49 and 1.75 for intermediate and high versus low consumption) and in GSTM1 null genotype (OR ¼ 1.18 and 1.02). These increases are statistically not significant. In postmenopausal women a suggestion of an effect of red meat consumption is observed: effects are slightly stronger, although still not statistically significant and without a clear dose-response relation: OR ¼ 1.79 (95% CI ¼ 0.92-3.50) and 1.46 (1.46 (95% CI ¼ 0.76-2.82) for intermediate and high compared to low red meat consumption respectively. Reliable evaluation of interaction is not possible due to the small number of cancers. Conclusion: GSTM1 null genotype increases breast cancer risk. Red meat consumption slightly increases breast cancer risk, but the relation is not statistically significant and GSTM1, NAT1, NAT2 and GSTT1 polymorphisms do not modify this relation.

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Molecular genetics of human polymorphic N-acetyltransferase: enzymatic analysis of 15 recombinant wild-type, mutant, and chimeric NAT2 allozymes

Cited by 104 publications

References 0 publications

Pharmacogenetics of the arylamine N-acetyltransferases

Pharmacogenetics of the arylamine N-acetyltransferases

N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk

GSTM1 Null Genotype, Red Meat Consumption and Breast Cancer Risk (The Netherlands)

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