Metabolism of food-derived heterocyclic amines in nonhuman primates

Elizabeth G. Snyderwine, Robert J. Turesky, Ken W Turteltaub, Cindy D. Davis, Nakissa Sadrieh, Herman A J Schut, Minako Nagao, Takashi Sugimura, Unnur P. Thorgeirsson, Richard H. Adamson, Snorri S. Thorgeirsson

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48 Scopus citations

Abstract

During the cooking of meats, several highly mutagenic heterocyclic amines (HCAs) are produced. Three HCAs, IQ, MeIQx, and PhIP have been under study for carcinogenicity in cynomolgus monkeys, and to date, IQ has been shown to be a potent hepatocarcinogen. Concomitantly, the metabolic processing of these HCAs has been examined. Metabolism studies show that the potent hepatocarcinogenicity of IQ is associated with the in vivo metabolic activation of IQ via N-hydroxylation and the formation of DNA adducts. In monkeys undergoing carcinogen bioassay with IQ, N-hydroxylation was confirmed by the presence of the N-hydroxy-N-glucuronide conjugate of IQ in urine. The N-hydroxylation of IQ appears to be carried out largely by hepatic CYP3A4 and/or CYP2C9/10, and not by CYP1A2, an isoform not expressed in liver of this species. Notably MeIQx is poorly activated in cynomolgus monkeys and lacks the potency of IQ to induce hepatocellular carcinoma after a 5-year dosing period. The poor activation of MeIQx appears to be due to the lack of constitutive expression of CYP1A2 and an inability of other cytochromes P450, such as CYP3A4 and CYP2C9/10, to N-hydroxylate the quinoxalines. MeIQx is detoxified in monkeys largely by conjugation with glucuronide at the N-1 position. Although the carcinogenicity of PhIP is not yet known,the metabolic data suggest that PhIP will be carcinogenic in this species. PhIP is metabolically activated in vivo in monkeys by N-hydroxylation, as discerned by the presence of the N-hydroxy-N-glucuronide conjugate in urine, bile, and plasma. PhIP also produces DNA adducts that are widely distributed in tissues. The results from these studies support the importance of N-hydroxylation in the carcinogenicity of HCAs in nonhuman primates and by analogy, the importance of this metabolic activation step in the possible carcinogenicity of dietary HCAs in humans.

Original languageEnglish (US)
Pages (from-to)203-210
Number of pages8
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume376
Issue number1-2
DOIs
StatePublished - May 12 1997
Externally publishedYes

Keywords

  • DNA adducts
  • Food carcinogen
  • IQ
  • MeIQx
  • Metabolism
  • PhIP

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Molecular Biology

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  • Cite this

    Snyderwine, E. G., Turesky, R. J., Turteltaub, K. W., Davis, C. D., Sadrieh, N., Schut, H. A. J., Nagao, M., Sugimura, T., Thorgeirsson, U. P., Adamson, R. H., & Thorgeirsson, S. S. (1997). Metabolism of food-derived heterocyclic amines in nonhuman primates. Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, 376(1-2), 203-210. https://doi.org/10.1016/S0027-5107(97)00044-4