Effect of dexamethasone and cytochrome P 450 inhibitors on the formation of 7α-hydroxydehydroepiandrosterone by human adipose stromal cells

Abstract

7α-Hydroxydehydroepiandrosterone (7α-OHDHA) is a major metabolite 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 P 450 inhibitors on the formation of 7α-OHDHA. Dexamethasone (10 −9 to 10 −7 M) stimulated 7α-OHDHA formation in a dose-dependent manner with a 2- to 5-fold stimulation at 10 −7 M. The dexamethasone stimulated 7α-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 7α-OHDHA formation suggesting that the dexamethasone stimulation was acting through the glucocorticoid receptor. Conversion of DHA to 7α-OHDHA was inhibited by ketoconazole and metyrapone. An inhibition of 70–80% was obtained with ketoconazole and 25–60% with metyrapone at concentrations of 10 −5 M. Aminoglutethimide phosphate was less effective than either ketoconazole or metyrapone in inhibiting 7α-OHDHA formation with <30% inhibition at 10 −5 M. These studies indicate that 7-hydroxylation provides an alternative pathway for the metabolism of DHA in peripheral tissues. This pathway, which is regulated by glucocorticoids, may influence the amount of DHA available for conversion to androstenedione and its subsequent aromatization to estrone. The biological role of the 7-oxygenated metabolites and their effects on other steroidogenic pathways have not been established.