EFFECT OF DEXAMETHASONE AND CYTOCHROME-P450 INHIBITORS ON THE FORMATION OF 7-ALPHA-HYDROXYDEHYDROEPIANDROSTERONE BY HUMAN ADIPOSE STROMAL CELLS

7 alpha-Hydroxydehydroepiandrosterone (7 alpha-OHDHA) is a major metab olite of dehydroepiandrosterone (DHA) using adipose stromal cells. To gain a better understanding of the factors regulating DHA metabolism, we examined the effect of dexamethasone and cytochrome P450 inhibitors on the formation of 7 alpha-OHDHA. Dexamethasone (10(-9) to 10(-7) M) stimulated 7 alpha-OHDHA formation in a dose-dependent manner with a 2- to 5-fold stimulation at 10(-7) M. The dexamethasone stimulated 7 a lpha-OHDHA formation was inhibited by RU486 in a dose-dependent manner with suppression to basal levels at 10(-6) M. Progesterone (10(-7) M) had no effect on 7 alpha-OHDHA formation suggesting that the dexameth asone stimulation was acting through the glucocorticoid receptor. Conv ersion of DHA to 7 alpha-OHDHA was inhibited by ketoconazole and metyr apone. An inhibition of 70-80% was obtained with ketoconazole and 25-6 0% with metyrapone at concentrations of 10(-5) M. Aminoglutethimide ph osphate was less effective than either ketoconazole or metyrapone in i nhibiting 7 alpha-OHDHA formation with <30% inhibition at 10(-5) M. Th ese studies indicate that 7-hydroxylation provides an alternative path way for the metabolism of DHA in peripheral tissues. This pathway, whi ch is regulated by glucocorticoids, may influence the amount of DHA av ailable for conversion to androstenedione and its subsequent aromatiza tion to estrone. The biological role of the 7-oxygenated metabolites a nd their effects on other steroidogenic pathways have not been establi shed.