STUDIES ON SEX DIFFERENCES IN THE O-DEALKYLATION ACTIVITIES OF 7-HYDROXYCOUMARIN O-ALKYL DERIVATIVES IN LIVER MICROSOMES OF RATS

Abstract

This chapter presents studies on sex differences in the O–dealkylation activities of 7–hydroxycoumarin O–alkyl derivatives in liver microsomes of rats. There are marked sex differences in the activities of drug metabolizing enzymes in rat liver microsomes although the magnitude depends on the substrate employed. To clarify the mechanism of sex difference, the study described in the chapter was initiated using 7–hydroxycoumarin O–methyl–, O–ethyl– and O–propyl– derivatives as substrates. It was found that the magnitude of the sex difference was remarkable in the O–depropylation activity. The chapter presents evidence that one or more species of cytochrome P-450 that is not sensitively inhibited by 7, 8–benzoflavone is involved in the occurrence of sex difference. 7, 8–benzoflavone was used as a specific inhibitor of a drug metabolizing enzyme inducible by polycyclic hydrocarbons such as 3–methylcholanthrene (MC). It showed that the O–depropylation activity was induced by treatment with MC. Thus, the effects of 7, 8–benzoflavone on the sex difference were examined using microsomes from phenobarbital (PB)–and MC–treated microsomes.