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

Abstract

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.

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

“…28 It has been shown that rate of N-acetylation to detoxify the aromatic amines is less in slow acetylators so these carcinogens are accumulated in the affected tissue. 8 The codon 751 polymorphism, which may change the activity of the enzyme, is located in COOH terminal domain of XPD. This region of the protein possesses helicase activity and deletion in this region causes reduced XPD DNA helicase activity.…”

“…Since polymorphisms at 481 and 803 np do not change the acetylation status so variant alleles/haplotypes, having at least one variant nucleotide at one of the remaining 3 polymorphic sites (341, 590 and 857 np), are known as slow acetylating alleles (e.g., NAT2*5B, NAT2*6B, NAT2*7A, etc). 8 So, individuals carrying 2 rapid acetylating alleles (such as NAT2*4/NAT2*4 genotype) in the pair of chromosomes are rapid acetylators; carrying 2 slow acetylating alleles (such as NAT2*5A/ NAT2*5B genotype) are slow acetylators; and carrying one slow and one rapid acetylating allele (i.e., NAT2*4/NAT2*5A genotype) is intermediate acetylators.…”

“…22 Instead of analyzing the genotype data at these 5 polymorphic sites separately, they were expressed as alleles/haplotypes, such as NAT2*4, NAT2*5A, NAT2*5B, NAT2*5C, NAT2*6B, NAT2*6C, NAT2*7A, NAT2*12B, NAT2*12C, etc., depending on the arrangements of nucleotides (T > C, C > T, G > A, A > G, G > A) at the above-mentioned 5 polymorphic sites. 8,23 These alleles/haplotypes will provide information of nucleotides present at these polymorphic sites at a glance and allelic combination or genotype will be used to determine the acetylation status of an individual. If an individual had only homozygous wild or variant genotypes at 1, 2, 3, 4 or 5 sites of these 5 polymorphic positions then allelic combination or genotype of that individual could be ascertained easily looking at the genotype data at 5 polymorphic sites of that individual.…”

“…6,7 Again, NAT2 slow acetylation increased the risk of bladder cancer, probably owing to slow acetylation at N-position of aromatic amines (such as 4-amino biphenyl), resulting in accumulation in the affected tissue. 8 A few studies, with small sample sizes, also observed positive associations between NAT2 slow acetylation status and risk of head and neck cancer. 9,10 This association was not reproduced in subsequent studies except for a subset of samples.…”

Genetic variation in N-acetyltransferase 1 (NAT1) and 2 (NAT2) and risk of non-Hodgkin lymphoma

“…NAT2 acetylation phenotype was assigned at the University of Louisville (by DWH) based on in vivo and in vitro data on allelic variation in catalytic activity [13]. For analysis of NAT2 phenotypes, individuals homozygous for NAT2 rapid-and slow-acetylator alleles were designated as rapid-and slow-acetylators, respectively; individuals possessing one rapid-and one slow-acetylator allele (heterozygotes) were designated as intermediate-acetylators [26].…”