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.

Figure 1

Each bar represents Mean ± SE for cytosolic N-acetyltransferase activities towards the aromatic amine urinary bladder carcinogens 4-aminobiphenyl (ABP) and ß -naphthylamine (BNA) in congenic Syrian hamsters with homozygous rapid acetylator genotype (black), heterozygous acetylator genotype (gray) or homozygous slow acetylator genotype (white). Differences among the genotypes were highly significant (p<0.0001) following one way analysis of variance. Adapted from Hein et al., 1994a; .

Figure 2

Each bar represents Mean ± SE for urinary excretion ratio of N-acetyl-p-aminobenzoic acid to p-aminobenzoic acid in Syrian hamsters with homozygous rapid acetylator genotype (black), heterozygous acetylator genotype (gray) or homozygous slow acetylator genotype (white). Differences among the genotypes were highly significant (p<0.0001) following one way analysis of variance. Adapted from Hein et al., 1994a.

Figure 3

Each bar represents Mean ± SD for the isoniazid elimination rate constant (top) or the area under the concentration-time curve (bottom) following a single oral dose of 5 or 10 mg/kg isoniazid in individuals with homozygous rapid acetylator genotype (black), heterozygous acetylator genotype (gray) or homozygous slow acetylator genotype (white). NAT2 genotypes and phenotypes were 100% concordant and differences among the genotypes were highly significant (p<0.0001) following one way analysis of variance. Adapted from Parkin et al., 1997.

Figure 4

Each bar represents Mean ± SE for cytosolic O-acetyltransferase activities towards N-hydroxy-4-aminobiphenyl (N-OH-ABP) in congenic Syrian hamsters with homozygous rapid acetylator genotype (black) or homozygous slow acetylator genotype (white). Differences between rapid and slow acetylators were significant in each tissue. Modified from Hein et al., 2006.

Figure 5

Rapid acetylator NAT2 allelic (haplotype) frequencies reported in various populations. Data for each population was derived from the following sources: Germany (Cascorbi et al., 1999); Spain (Agundez et al., 1996); United Kingdom (UK); (Loktionov et al., 2002); Poland (Lan et al., 2003); Holland (van der Hel et al., 2003); USA Caucasian (Deitz et al., 2000); Nigeria (unpublished data from author’s laboratory); South Africa (Loktionov et al., 2002); Africa (Delomenie et al., 1996); USA Black (O’Neill et al., 2000); South India (Anitha and Banerjee, 2003) and Korea (Lee et al., 2002).

Figure 6

Slow acetylator NAT2 allelic (haplotype) frequencies reported in various populations. Data for each population was derived from the same sources listed in Figure 5.

Figure 6

Slow acetylator NAT2 allelic (haplotype) frequencies reported in various populations. Data for each population was derived from the same sources listed in Figure 5.

Figure 7

Meta-analysis of NAT2 slow acetylator genotype and bladder cancer risk. Odds ratios (circles) with 95% confidence limits (bars) represent the association of slow NAT2 acetylator phenotype/genotype with urinary bladder cancer reported in various studies throughout the world. Studies carried out in various countries are listed in ascending order of case size which is represented visually by circle size. Group analyses of the world total, and of European, American, and Asian subgroups are shown. Modified with permission from Garcia-Closas et al., 2005.