Inhibition of testosterone biosynthesis by ethanol: multiple sites and mechanisms in dispersed Leydig cells.
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/l ethanol reduced the concentration of testosterone (16%, P less than 0.025); raised the concentrations of pregnenolone (60%, P less than 0.001), androstenedione (86%, P less than 0.001) and dehydroepiandrosterone (81%, P less than 0.001); but did not change concentrations of progesterone and 17 alpha-hydroxyprogesterone in the incubation medium. Ethanol also raised the lactate/pyruvate ratio in the Leydig cell suspension. 4-Methylpyrazole (0.5 mmol/l) 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 3 beta-hydroxy-5-ene-steroid dehydrogenase/5-ene-4-ene-isomerase catalyzed reactions and the conversion of androstenedione 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 3 beta-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.
D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D003864:Depression, Chemical; D000431:Ethanol / Q000494:pharmacology*; D012739:Gonadal Steroid Hormones / Q000096:biosynthesis; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D011375:Progesterone Reductase / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D013256:Steroids / Q000096:biosynthesis; D013739:Testosterone / Q000096:biosynthesis*
D006063:Chorionic Gonadotropin; D012739:Gonadal Steroid Hormones; D013256:Steroids; D009243:NAD; D000431:Ethanol; D013739:Testosterone; D000735:Androstenedione; D015096:3-Hydroxysteroid Dehydrogenases; D011375:Progesterone Reductase