Acetylator genotype and arylamine-induced carcinogenesis.

A diverse array of arylamine chemicals derived from industry, diet, cigarette smoke and other environmental sources are carcinogenic. These chemicals require metabolic activation by host enzymes to chemically reactive electrophiles to initiate the carcinogenic response. Genetic regulation of activation and/or deactivation pathways are thought to account in large measure for corresponding differences in tumor incidence from these chemicals between tissues, between species, or between individuals within a species. Various acetyltransfer reactions are involved in arylamine metabolism and much has been learned regarding their enzymology, genetic regulation, and toxicological significance. The small amount of human data are supported by systematic investigations carried out in animal models characterized with respect to the acetylation polymorphism. Enzymological and genetic investigations suggest that common enzymes encoded by the acetyltransferase gene carry out a diverse set of acetyltransferase reactions. Thus, the acetylation polymorphism can influence both activation and deactivation pathways in arylamine metabolism. Of particular significance recently have been reports documenting the O-acetylation of N-hydroxyarylamine carcinogens and its genetic coregulation with the well-characterized arylamine N-acetylation polymorphism. The toxicological consequences of this polymorphic pathway have yet to be fully explored. Epidemiological investigations show associations between acetylator phenotype and the incidence and/or severity of tumors in the urinary bladder, colon and larynx. Associations between acetylator phenotype and breast cancer are more equivocal and require further study. The divergent influence of acetylator phenotype on the incidence of tumors in different organ sites suggests an important role for extrahepatic acetyltransferases, and further characterization of them in human and animal tissues is needed. The advent of newer methodologies to monitor chemical exposures and to measure acetylator phenotype (rapid, intermediate and slow) using less invasive and more standardized protocols should soon result in a much more definitive understanding regarding the role of acetylator status in arylamine-induced carcinogenesis.