METABOLIC-ACTIVATION AND GENOTOXICITY OF HETEROCYCLIC ARYLAMINES

Because of the potential for human exposure to mutagenic and carcinoge nic heterocyclic arylamines in the diet, the carcinogenicity of three HAAs, 2-amino-3-methylimidazo[4,5-f]quinoline, 2-amino-3,8-dimethyl-im idazo[4,5-f]quinoxaline, and 2-amino-1-methyl-6-phenylimidazo]4,5-b]pr yidine, is being evaluated in nonhuman primates, especially cynomolgus monkeys. Concomitant with the carcinogenicity studies, the metabolic processing, disposition, and DNA-adduct formation of these compounds a re being examined in these monkeys. This report highlights the results from studies in monkeys and from in vitro models examining metabolic activation and genotoxicity of HAAs. The extent of in vivo activation of HAAs in monkeys was assessed by measuring DNA adducts in various ti ssues. Both 2-amino-3-methylimidazo[4,5-b]quinoline and 2-amino-1-meth yl-6-phenylimidazo[4,5-b]pyridine form high levels of DNA adducts in a number of organs, particularly the liver, kidney, and heart. The impl ications of metabolic activation and DNA-adduct formation to the carci nogenicity of HAAs are discussed.