METABOLIC PROCESSING AND DNA ADDUCTION OF HETEROCYCLIC AMINE FOOD MUTAGENS

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Through extensive research with nonhuman primates, we have established that metabolic activation of the heterocyclic amines (HAs) is essential for carcinogenicity. N-Hydroxylation via cytochrome P-450s is the most critical enzyme influencing HA carcinogenicity. Using 2-amino-3,8- dimethylimidao[4,5-f]quinoxaline (MeIQx), we have demonstrated that the lack of carcinogenicity of MeIQx in nonhuman primates is due to its poor P450-mediated metabolic activation in vivo. In contrast, the potent carcinogenicity of 2-amino-3- methylimidazo[4,5-f]quinoline (IQ) is associated with its being metabolically activated in the monkey by cytochrome P-450 mediated N-hydroxylation. The metabolic activation leading to carcinogenicity of IQ in nonhuman primates is carried out by two major cytochromes: CYP3A4 and CYP2C. These cytochromes show a select substrate specificity for the metabolic activation of IQ over MeIQx. We further examined the metabolic processing of MeIQx in vivo in monkeys and identified several novel metabolites indicative of pathways of MeIQx detoxification which may be useful as metabolic biomarkers in humans. DNA adducts and their role in carcinogenicity, toxicity, and mutagenicity were investigated. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-DNA adducts are widely distributed in tissues of cynomolgus monkey, indicating that PhIP, similar to IQ, is a probable carcinogen in this species. High PhIP-DNA adduct levels were observed in the heart of cynomolgus monkeys. An in vitro cardiomyocyte model and a rat model were established to study the cardiotoxicity of the HAs. Our findings showed that the N-hydroxylamine metabolites of IQ and PhIP were cardiotoxic, but that this toxicity was independent of DNA adduct formation. N-acetyl- cysteine and other antioxidants were found to largely prevent HA-induced cardiotoxicity. The involvement of a free radical mechanisms in HA cardiotoxicity, which might also be relevant for explaining the carcinogenicity of these compounds, was hypothesized.