Inhibition of testosterone biosynthesis by ethanol: Multiple sites and mechanisms in dispersed leydig cells

Abstract

Isolated rat Leydig cells were incubated for 2 h in sealed polycarbonate tubes under O2/CO2 atmosphere with 10 mIU/ml human chorionic gonadotropin. 20 mmol/1 ethanol reduced the concentration of testosterone (16%, P <0.025); raised the concentrations of pregnenolone (60%, P <0.001), androstenedione (86%, P<0.001) and dehydroepiandrosterone (81%, P<0.001); but did not change concentrations of progesterone and 17α -hydroxyprogesterone in the incubation medium. Ethanol also raised the lactate/pyruvate ratio in the Leydig cell suspension. 4-Methylpyrazole (0.5 mmol/1) abolished the ethanol-induced changes. The present results suggest that ethanol inhibits testosterone synthesis in isolated rat Leydig cells at the pregnenolone-to-testosterone pathway by inhibiting 3β-hydroxy-5-ene-steroid dehydrogenase/5-ene-4-ene-isomerase catalyzed reactions and the conversion of adrostenedione to testosterone. These inhibitions are caused by consequences of ethanol metabolism. A likely mechanism for the former inhibition is that the increase in the NADH/NAD+ ratio in Leydig cells leads to inhibition of reactions catalyzed by 3β-hydroxy-5-ene-steroid dehydrogenase/5-ene-4-ene isomerase, but the inhibition mechanism operating at the androstenedione-to-testosterone step remains to be characterized. © 1987.