Sex-specific cytochrome P450 as a cause of sex- and species-related differences in drug toxicity.

Male rats are the most frequently used experimental animals in drug toxicity tests. However, there are clear sex-related differences in toxicity of various drugs and chemicals in rats. These differences, in most cases, are closely connected with the sex-related differences in hepatic drug metabolisms. Recent studies indicate the existence of sex-specific cytochrome P450, such as P450-male (2C11) and P450-female (2C12) and P450(6) beta (3A2) in rat livers, and also show that their expression levels are markedly different between male and female rats. The expressions of sex-specific P450s are regulated by growth hormone, thyroid hormone, sex hormones and other chemicals. On the other hand, there are no or few cytochrome P450s that show the sex-related differences in species other than rats and mice. Although there are orthologous cytochrome P450s in viewpoints of amino acid sequence and substrate specificity in experimental animal species and humans, their expressions are not regulated by hormonal factors in most of the species. These differences may cause clear species differences, if male animals are used, in the toxicity caused by various drugs and chemicals. Thus we can predict the sex-related difference in drug toxicity on the basis of difference in the expression levels of sex-specific cytochrome P450s.