Sex-dependent metabolism of xenobiotics

Drug Metabolism Reviews
C A Mugford, G L Kedderis

Abstract

Sex-dependent differences in xenobiotic metabolism have been most extensively studied in the rat. Because sex-dependent differences are most pronounced in rats, this species quickly became the most popular animal model to study sexual dimorphisms in xenobiotic metabolism. Exaggerated sex-dependent variations in metabolism by rats may be the result of extensive inbreeding and/or differential evolution of isoforms of cytochromes P450 in mammals. For example, species-specific gene duplications and gene conversion events in the CYP2 and CYP3 families have produced different isoforms in rats and humans since the species division over 80 million years ago. This observation can help to explain the fact that CYP2C is not found in humans but is a major subfamily in rats (Table 11). Animal studies are used to help determine the metabolism and toxicity of many chemical agents in an attempt to extrapolate the risk of human exposure to these agents. One of the most important concepts in attempting to use rodent studies to identify sensitive individuals in the human population is that human cytochromes P450 differ from rodent cytochromes P450 in both isoform composition and catalytic activities. Xenobiotic metabolism by male rats can reflect...Continue Reading

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