IMPROVEMENT OF CYTOCHROME P450C17 CATALYTIC PROCESSIVITY AS A NOVEL MECHANISM TO ATTENUATE HORMONAL CONSEQUENCES OF ENZYME DECAY IN THE TESTES AFTER A GONADOTROPIN SURGE

Objective: The aim of this study was to gain understanding of the appa rent discrepancy between the moderate restriction of testosterone synt hesizing capacity and the nearly complete decay of the androgen-produc ing enzyme, cytochrome P450c17 (CYP17; steroid 17 alpha-hydroxylase/17 ,20-lyase), in rat testes during the desensitization phase induced by a single, high-dose gonadotropin (human chorionic gonadotropin, hCG) i njection. Design and methods: Adult male rats received 25 IU hCG i.v., and purified Leydig cells and crude interstitial cell microsomes were prepared 0, 4, 12, 24, 48, 72, 120 and 192 h afterwards. Component CY P17 activities, i.e. simultaneously catalyzed productive androgen form ation and abortive 17 alpha-hydroxyprogesterone release, and their rat io (processivity), were compared with CYP17 levels and testosterone se cretion rates. Results: Leydig cells isolated 48 h after the artificia l hCG surge produce 62% less testosterone than control cells upon stim ulation in vitro, though CYP17 levels are reduced by 97%. Its total ac tivity decreases by 87%, resulting in a 4.5-fold rise in the turnover number; the processivity is additionally improved 5-fold over controls . Parallel changes occur in interstitial cell microsomes; a negative l inear correlation exists between the ratio of productive over total CY P17 activities and the actual CYP17 concentrations, CYP17 is partly de natured to P420 during hCG action, but other heme proteins (cytochrome b5) remain unchanged. Animal treatment with estradiol results in CYP1 7 downregulation without any concomitant effect on enzyme processivity . Conclusion: Improved CYP17 processivity is suggested to be the conse quence of (otherwise rate-limiting) improved electron transfer efficie ncy towards CYP17. It explains the relatively high testosterone secret ion during Leydig cell desensitization and is interpreted to be a prot ective mechanism to confine adverse consequences of enzyme decay.