Estradiol Acts as a Competitive Inhibitor of the 3β-Hydroxysteroid Dehydrogenase/Δ5-Δ4Isomerase Enzyme of Cultured Leydig Tumor Cells*

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Abstract
To study the local regulatory mechanisms involving steroid hormones in steroidogenic cells, the effect of estradiol on steroidogenesis was investigated using MA-10 Leydig tumor cells. Estradiol inhibited progesterone biosynthesis in MA-10 cells in a dose-dependent manner. Inhibition of progesterone biosynthesis by estradiol was associated with a concomitant accumulation of pregnenolone in the incubation medium. Estradiol inhibited the activity of 3.beta.-hydroxysteroid dehydrogenase/.DELTA.5/.DELTA.4 isomerase by a chemical mechanism which is not mediated through the cellular estrogen receptor. Thus, the estrogen receptor agonist diethylstilbestrol did not inhibit this enzyme activity, nor could this agent block the effect of estradiol on the enzyme. Furthermore, estradiol inhibited enzyme activity in isolated microsomes which do not contain estradiol receptor protein. Kinetic analysis of the inhibitory effect of estradiol on 3.beta.-hydroxysteroid dehydrogenase/.DELTA.5-.DELTA.4 isomerase revealed that this steroid hormone functions as a competitive inhibitor of the enzyme, with an average apparent Ki of 1.8 .mu.M.
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