Sex-Dependent Metabolism of Xenobiotics (1998) (Published as Appx P4 of UDP Peer Panel Report)
نویسندگان
چکیده
Sex-dependent differences in xenobiotic metabolism are most pronounced in rats. Consequently, 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 or differential evolution of cytochrome P450 (CYP) isoforms in mammals. Sex-dependent differences in other xenobiotic-metabolizing enzymes such as sulfotransferases, glutathione transferases, and glucuronyltransferases have also been observed. Animal studies are used to help determine the metabolism and toxicity of many chemical agents in an attempt to extrapolate the risk to humans from exposure to these agents. One of the most important concepts to consider in using rodent studies to identify sensitive individuals in the human population is that human CYPs differ from rodent CYPs in both isoform composition and catalytic activities. Metabolism of xenobiotics by male rats can reflect human metabolism when the compound of interest is metabolized by CYP1A or CYP2E because there is strong regulatory conservation of these isoforms between rodents and humans. However, problems can arise when rats are used as animal models to predict the potential for sex-dependent differences in xenobiotic handling in humans. Information from numerous studies has shown that the identification of sex-dependent differences in metabolism by rats does not translate across other animal species or humans. To date, sex-specific isoforms of CYP have not been identified in humans. This lack of expression of sex-dependent isoforms in humans indicates that the male rat is not an accurate model for the prediction of sex-dependent differences in humans. Differences in xenobiotic metabolism among humans are more likely the consequence of intraindividual variations as a result of genetics or environmental exposures rather than being due to sexdependent differences in enzyme composition.
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