Sex-dependent metabolism of xenobiotics.

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 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 countless studies has shown that the identification of sex-dependent differences in metabolism by rats does not translate across other animal species or humans. The major factor contributing to this observation is that CYP2C, a major subfamily in rats, which is expressed in a sex-specific manner, is not found in humans. To date, sex-specific isoforms of cytochromes P450 have not been identified in humans. The 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 from sex-dependent differences in enzyme composition. A major component of the drug discovery and development process is to identify, at as early a stage as possible, the potential for toxicity in humans. Earlier identification of individual differences in xenobiotic metabolism and the potential for toxicity will be facilitated by improving techniques to make better use of human tissue to prepare accurate in vitro systems such as isolated hepatocytes and liver slices to study xenobiotic metabolism and drug-induced toxicities. Accurate systems should possess an array of bioactivation enzymes similar to the in vivo expression of human liver. In addition, the compound concentrations and exposure times used in these in vitro test systems should mimic those achieved in the target tissues of humans. Consideration of such factors will allow the development of compounds with improved efficacy and low toxicity at a more efficient rate. The development of accurate in vitro systems utilizing human tissue will also aid in the investigation of the molecular mechanisms by which the CYP genes are regulated in humans. Such studies will facilitate the study of the basis for differences in expression of isoforms of CYP450 in humans.