Metabolic processing and carcinogenicity of heterocyclic amines in nonhuman primates

Abstract

The potential for human exposure to heterocyclic amine (HAA) mutagens derived from cooking food prompted an evaluation of the disposition and carcinogenicity of three of the HAAs in nonhuman primates, especially cynomolgus monkeys. The three HAAs currently under study are 2-amino-3-methylimidazo [4, 5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx) and 2-amino-1-methyl-6-phenylimidazo [4,5,b]pyridine (PhIP). These three HAAs were selected on the basis of several factors including structure, mutagenic activity in vitro, concentration in cooked meat, activity in rodent carcinogenicity tests and availability. Studies on the disposition of IQ demonstrated that it was extensively metabolized in monkeys and excreted in urine and feces as metabolites. These metabolites represent predominantly detoxification products of IQ. The extent of in vivo activation of IQ and PhIP was assessed by measuring DNA adducts in various tissues and white blood cells of monkeys following administration of the compounds. Both compounds form high levels of DNA adducts in a number of organs, particularly the liver, kidney, and heart. The carcinogenicity of IQ, 8-MeIQx and PhIP in nonhuman primates has been under study for 5 years, 24 months, and 7 months, respectively. Thus far, IQ has induced hepatocellular carcinoma in 3 of 20 monkeys at doses of 10 mg/kg daily, 5 days/week and in 10 of 20 monkeys at 20 mg/kg on the same schedule. Thus, IQ is a potent liver carcinogen in nonhuman primates and a potential carcinogen for humans.