ABSTRACT
N-acetyltransferases (EC 2.3.1.5) catalyze O-acetylation of heterocyclic amine carcinogens to DNA-reactive electrophiles that bind and mutate DNA. An acetylation polymorphism exists in humans and Syrian hamsters regulated by N-acetyltransferase-2 (NAT2) genotype. Some human epidemiological studies suggest a role for NAT2 phenotype in predisposition to cancers related to heterocyclic amine exposures, including breast cancer. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic amine carcinogen prevalent in the human environment and induces a high incidence of mammary tumors in female rats. PhIP-induced carcinogenesis was examined in female rapid and slow acetylator Syrian hamsters congenic at the NAT2 locus. In both rapid and slow acetylators, PhIP-DNA adduct levels were highest in pancreas, lower in heart, small intestine, and colon, and lowest in mammary gland and liver. Metabolic activation of N-hydroxy-PhIP by O-acetyltransferase was highest in mammary epithelial cells, lower in liver and colon, and lowest in pancreas. Metabolic activation of N-hydroxy-PhIP by O-sulfotransferase was low in liver and colon and below the limit of detection in mammary epithelial cells and pancreas. Unlike the rat, PhIP did not induce breast or any other tumors in female rapid and slow acetylator congenic hamsters administered high-dose PhIP (10 doses of 75 mg/kg) and a high-fat diet.
Subject(s)
Carcinogens/toxicity , DNA Adducts/drug effects , Imidazoles/toxicity , Mammary Neoplasms, Experimental/chemically induced , Acetylation , Administration, Oral , Animals , Animals, Congenic , Arylamine N-Acetyltransferase/genetics , Carcinogens/administration & dosage , Cricetinae , DNA Adducts/metabolism , Disease Models, Animal , Female , Homozygote , Imidazoles/administration & dosage , Imidazoles/metabolism , Mammary Glands, Animal/drug effects , Mammary Glands, Animal/metabolism , Mammary Glands, Animal/pathology , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/pathology , Mesocricetus , Tissue DistributionABSTRACT
The focus of this review is the molecular genetics, including consensus NAT1 and NAT2 nomenclature, and cancer epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Two N-acetyltransferase isozymes, NAT1 and NAT2, are polymorphic and catalyze both N-acetylation (usually deactivation) and O-acetylation (usually activation) of aromatic and heterocyclic amine carcinogens. Epidemiological studies suggest that the NAT1 and NAT2 acetylation polymorphisms modify risk of developing urinary bladder, colorectal, breast, head and neck, lung, and possibly prostate cancers. Associations between slow NAT2 acetylator genotypes and urinary bladder cancer and between rapid NAT2 acetylator genotypes and colorectal cancer are the most consistently reported. The individual risks associated with NAT1 and/or NAT2 acetylator genotypes are small, but they increase when considered in conjunction with other susceptibility genes and/or aromatic and heterocyclic amine carcinogen exposures. Because of the relatively high frequency of some NAT1 and NAT2 genotypes in the population, the attributable cancer risk may be high. The effect of NAT1 and NAT2 genotype on cancer risk varies with organ site, probably reflecting tissue-specific expression of NAT1 and NAT2. Ethnic differences exist in NAT1 and NAT2 genotype frequencies that may be a factor in cancer incidence. Large-scale molecular epidemiological studies that investigate the role of NAT1 and NAT2 genotypes and/or phenotypes together with other genetic susceptibility gene polymorphisms and biomarkers of carcinogen exposure are necessary to expand our current understanding of the role of NAT1 and NAT2 acetylation polymorphisms in cancer risk.
