Metabolism and biodisposition of heterocyclic amines.

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Abstract

The metabolic pathways of activation and detoxification of heterocyclic aromatic amines are similar to those reported for other aromatic amines. In vitro studies have shown that oxidation of the exocyclic amine group by cytochrome P450 results in formation of the mutagenic N-hydroxylamine derivatives. However, metastable conjugates of the hydroxyamino metabolites have not been identified in biological fluids such as bile or urine of rodents. This is in contrast to the aromatic amines 2-acetylaminofluorene and 4-aminobiphenyl in which both the hydroxamic acid and the N-glucuronide of the hydroxylamine have been identified (Miller et al., 1960; Radomski et al., 1973). This suggests that either very low levels of the N-hydroxyamino metabolites of heterocyclic amines are formed or that they are not stable and react rapidly. Phase II conjugation reactions include N-glucuronidation and the unusual pathway of sulfamate formation for several of these amines including IQ and MeIQx. Conjugation to glutathione has not been reported to be a major route of in vivo metabolism and detoxification of heterocyclic amines. Studies conducted in vitro are few and inconclusive. One study has shown that glutathione may serve both to activate as well as to detoxify hydroxyamino-Trp-P-2 (Saito et al., 1983). While a second study demonstrated that depletion of cellular glutathione increased the binding of Trp-P-2 metabolites to DNA in hepatocytes (Mita et al., 1982). Thus the role that glutathione plays in protecting the cell against this class of genotoxins merits further investigation. Much data has been gathered on human exposure to heterocyclic amines and mechanisms of genotoxicity have been elucidated, however, risk estimation of cancer development in humans by these carcinogens is still uncertain. There may be differences between man and rodents in the absorption, metabolism and activation versus detoxification as well as rates of excretion of heterocyclic amines. Humans also are exposed to many other carcinogens and potential tumor promoters (Sugimura, and Sato, 1983). Tumor promoters may enhance the effects of carcinogens. Fortunately, there also are tumor inhibiting factors in the diet which may weaken the biological activity of carcinogens (Wattenberg, 1985). Such variables make it difficult to extrapolate carcinogenicity data from animal experiments to assess risk to human cancer development.(ABSTRACT TRUNCATED AT 400 WORDS)

Original languageEnglish (US)
Pages (from-to)39-53
Number of pages15
JournalProgress in clinical and biological research
Volume347
StatePublished - Jan 1 1990

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