Medroxyprogesterone acetate and dexamethasone are competitive inhibitors of different human steroidogenic enzymes

Medroxyprogesterone acetate (MPA), a widely used progestin, can suppress th e hypolthalamic-pituitary-gonadal axis but can also directly inhibit gonada l steroidogenesis; the success of MPA as a treatment for gonadotropin-indep endent sexual precocity derives from its direct action on steroidogenic tis sues. Dexamethasone, a widely used glucocorticoid, can suppress the hypotha lamic-pituitary-adrenal axis, but its potential effect directly on the adre nal is unclear. Previous reports suggested that these two drugs may act on the initial steps in the rodent steroidogenic pathway; therefore, we invest igated their abilities to inhibit the first three human enzymes in steroido genesis: the cholesterol side-chain cleavage enzyme (P450c17), the 17 alpha -hydroxylase/17,20-lyase (P450c17), and type II SP-hydroxysteroid dehydroge nase/isomerase (3 beta HSDII). We found no effect of either drug on P450scc in intact human choriocarcinoma JEG-3 cells. Using microsomes from yeast e xpressing human P450c17 or microsomes from human adrenals, we found that de xamethasone inhibited P450c17 with a K-i of 87 mu mol/L, which is about 100 0 times higher than typical therapeutic concentrations, but that MPA has no detectable action on P450c17. Using microsomes from yeast expressing human 3 beta HSDII, we found that this enzyme has indistinguishable apparent K-m values of 5.2-5.5 mu mol/L and similar maximum velocities of 0.34-0.56 pmo l steroid/min.mu g microsomal protein for the three principal endogenous su bstrates, pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone. In this system, MPA inhibited 3 beta HSDII with a K-i of 3.0 mu mol/L, whi ch is near concentrations achieved by high therapeutic doses of 5-20 mg MPA /kg.day. These data establish the mechanism of action of MPA as an inhibito r of human steroidogenesis, and are in contrast with the results of earlier studies indicating that MPA inhibited both P450c17 and 3 beta HSD in rat L eydig cells, These studies establish the "humanized yeast" system ns a mode l for studying the actions of drugs on human steroidogenic enzymes and sugg est that 3 beta HSDII may be an appropriate target for pharmacological inte rventions in human disorders characterized by androgen excess or sex steroi d dependency.