The aim of the proposed studies is to test three interrelated hypotheses, with a goal ot elucidate the mechanism of action of catatoxic steroids and the biochemical basis for age- and sex- dependent differences in the pharmacologic and toxicologic response of rats to various drugs and chemical toxins. Catatoxic steroids are a group of steroidal agents that protect animals from the adverse effects of a large number of structurally diverse xenobiotics. Each of the three hypotheses to be tested depends on the purification of rat liver microsomal cytochromes P-450h and P-450p and the preparation of a library of epitope-specific monoclonal antibodies in mice. Cytochrome P-450p is the major form of cytochrome P-450 inducible by catatoxic steroids, whereas cytochrome P-450h is a male specific isozyme. Like cytochrome P-450h, high levels of cytochrome P-450p are constitutively expressed in adult male but not female rats. The first hypothesis to be tested is that certain age and sex differences in the response of rats to various drugs and chemical toxins are due to age and sex differences in the levels of liver microsomal cytochromes P-450h and/or P-450p. The second hypothesis to be tested is that the mechanism of action of catatoxic steroids is dependent on the induction of cytochrome P- 450p, which attenuates the adverse effects of xenobiotics by accelerating their metabolic inactivation. Three types of study are proposed to test these hypotheses; the first is an immunochemical study of the regulation of cytochromes P-450h and P-450p and of their role in the biotransformation of xenobiotics and testosterone. The second focusses on the effects of age and sex on the biologic/toxic effects of various xenobiotics in rats. The third focusses on the ability of the cytochrome P- 450p inhibitor, troleandomycin to reverse the protective effects of catatoxic steroids. If the hypotheses are correct, the proposed studies will have potential clinical application because several commonly used drugs induce a cytochrome P-450p-type hemoprotein in humans. The third hypothesis to be tested is that cytochrome P-450p is responsible for the 2 beta-, 6 beta-, 15 beta-and 18-hydroxylation of testosterone and the 4-hydroxylation of mephenytoin. There is considerable interindividual variation in mephenytoin 4-hydroxylase activity dure to a genetic polymorphism in humans. The correlation between testosterone hydroxylase and mephenytoin hydroxylase activity will be investigated for its potential value in the development of non- invasive test of the mephenytoin polymorphism in humans.
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