Molecular genetics and function of NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis

Abstract

Aromatic and heterocyclic amines require metabolic activation to electrophilic intermediates that initiate carcinogenesis. N-Acetyltransferase 1 (NAT1) and 2 (NAT2) are important enzymes in the biotransformation of these carcinogens and exhibit genetic polymorphism. Human NAT1 and NAT2 alleles are listed at: http://www.louisville.edu/medschool/pharmacology/NAT. html by an international gene nomenclature committee. The high frequency of the NAT1 and NAT2 acetylation polymorphisms in human populations together with ubiquitous exposure to aromatic and heterocyclic amines suggest that NAT1 and NAT2 acetylator genotypes are important modifiers of human cancer susceptibility. For cancers in which N-acetylation is a detoxification step such as aromatic amine-related urinary bladder cancer, NAT2 slow acetylator phenotype is at higher risk. Multiple studies have shown that the urinary bladder cancer risk is particularly high in the slowest NAT2 acetylator phenotype or genotype (NAT2 * 5). In contrast, for cancers in which N-acetylation is negligible and O-acetylation is an activation step such as for heterocyclic amine-related colon cancer, NAT2 rapid acetylator phenotype is at higher risk. Although studies have found associations between NAT1 genotype and various cancers, the findings are less consistent and are not well understood. Since cancer risk requires exposure to aromatic and/or heterocyclic amine carcinogens modified by NAT1 and/or NAT2 acetylator genotype, the results from human epidemiology studies are dependent upon the quality and accuracy of the exposure assessment and genotype determination. Conclusions require understanding the relationship between genotype and phenotype, as well as the role of genetic variation in carcinogen metabolism, DNA repair, and host susceptibility. Investigations have been carried out in rapid and slow acetylator rodent models in which both exposure and genetic variability are tightly controlled. Human NAT1 and NAT2 alleles have been characterized by recombinant expression to further understand the effects of nucleotide polymorphisms on function and phenotype.

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

“…Five of these ratios (0.3 and greater) correspond to rapid acetylators, and the other three (0.01-0.09, 0.1-0.19 and 0.2-0.29) correspond to different levels of slow acetylator phenotype. As reviewed previously (Hein, 2002), urinary bladder cancer risk increased as NAT2 metabolic ratio (phenotype) decreased (P trend ¼ 0.0006). The risk was markedly increased in the slowest NAT2 phenotype (OR,20.8;95% CI,.…”

“…NAT1 and NAT2 in animal models such as rabbit, mouse, Syrian hamster and rat are highly homologous to both human NAT1 and NAT2 (Hein et al, 1997;Hein, 2002). Substrate specificities for Syrian hamster, mouse and rat NAT2 may resemble human NAT1 more than they do human NAT2 .…”

“…The effects of NAT2 SNPs on catalytic activities have been investigated primarily in recombinant expression systems (reviewed in Hein et al, 2000;Hein, 2002). Nucleotide substitutions identified in human NAT2 allelic variants yield reductions in substrate affinity, catalytic activity and/or protein stability of the recombinant N-acetyltransferase allozymes.…”

SNPs in cancer research and treatment

“…The risk of developing urinary bladder cancer is particularly high in the slowest NAT2 acetylator phenotype, and is exacerbated by the history of smoking. On the other hand, for heterocyclic amine-related colon cancer, NAT2 rapid acetylator phenotype confers a higher risk (Golka et al, 2002;Hein, 2002).…”

Synergism between the N-acetyltransferase 2 gene and oxidant exposure increases the risk of idiopathic male infertility

“…Human NAT2 is expressed in the male reproduction system, including testicular tissues, prostate, genital ducts and exocrine glands where the enzyme may have a protective role against chemicals responsible for male urogenital diseases (Husain et al, 2007;Wu et al, 2013). In particular, the enzyme acetylates benzidine and 2-naphthylamine (harmful aromatic amines of cigarette smoke), 2-aminofluoren (a dye widely used in industry), hydrazine-containing drugs (isoniazid, simendan) and heterocyclic amines (chemicals in meat cooked at high temperatures) are derived from their metabolic activation by cytochrome P450 1A2 (Guengerich, 2000;Hein, 2002;Hein et al, 2000). NAT2 has also been found to activate carcinogens, thereby producing unstable electrophiles that may induce point mutations in DNA (Hein et al, 1993).…”