title: Adenosine 3',5'-monophosphate-mediated induction of 17 alpha-hydroxylase and C 17-20 lyase activities in cultured mouse Leydig cells is enhanced by inhibition of steroid biosynthesis.
abstract: We recently reported that treatment of mouse Leydig cell cultures for 5 days with LH or cAMP caused an induction of the microsomal cytochrome P-450 activities 17 alpha-hydroxylase and C17-20 lyase. We also have shown that the microsomal P-450s are very sensitive to oxygen-mediated loss of these activities and that this decrease is enhanced by steroids produced during acute cAMP stimulation of Leydig cells. In the present study, we investigated whether steroids produced during chronic cAMP treatment of Leydig cells limit the extent of induction of 17 alpha-hydroxylase and C17-20 lyase. Treatment of Leydig cell cultures with 8-bromo-cAMP in the presence of aminoglutethimide, an inhibitor of cholesterol side-chain cleavage, resulted in a 4- to 7-fold enhancement of cAMP-mediated induction of the 17 alpha-hydroxylase and C17-20 lyase activities and, after 11 days of treatment, completely restored the activities to those found in freshly isolated Leydig cells. Treatment with aminoglutethimide in the absence of cAMP had no effect on these enzyme activities. Addition of the steroid products androstenedione and/or testosterone (5 microM) to cAMP-plus amino-glutethimide-treated cultures caused a significant reduction in cAMP-mediated induction of microsomal P-450, while addition of estradiol (50 nM) had no significant effect. 3 beta-Hydroxysteroid dehydrogenase-isomerase, another microsomal enzyme that is not a P-450 enzyme, was not induced by cAMP in either the presence or absence of aminoglutethimide. The data suggest that Leydig cell microsomal P-450 activities are maintained in vivo by a balance between two processes: cAMP-mediated induction and steroid product-induced degradation.
mesh_terms: D000446:Aldehyde-Lyases / Q000378:metabolism*; D000616:Aminoglutethimide / Q000494:pharmacology*; D000735:Androstenedione / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism; D007985:Leydig Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008861:Microsomes / Q000201:enzymology; D013254:Steroid 17-alpha-Hydroxylase / Q000096:biosynthesis*; D013250:Steroid Hydroxylases / Q000096:biosynthesis*; D013739:Testosterone / Q000096:biosynthesis / Q000494:pharmacology
chemical_list: D000616:Aminoglutethimide; D013739:Testosterone; D000735:Androstenedione; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D000242:Cyclic AMP; D006913:Hydroxysteroid Dehydrogenases; D013250:Steroid Hydroxylases; D013254:Steroid 17-alpha-Hydroxylase; D000446:Aldehyde-Lyases