Destruction of testicular cytochrome P-450 by 7 alpha-thiospironolactone is catalyzed by the 17 alpha-hydroxylase.
Studies were done to determine the role of the 17 alpha-hydroxylase in the conversion of 7 alpha-thiospironolactone (7 alpha-thio-SL) to a reactive metabolite causing the degradation of testicular cytochrome P-450. Incubation of guinea pig testicular microsomes with 7 alpha-thio-SL plus NADPH resulted in an approx. 70% decline in cytochrome P-450 content and even greater loss of 17 alpha-hydroxylase activity. Addition of the 17 alpha-hydroxylase inhibitor, SU-10'603, to the incubation medium prevented the degradation of P-450 by 7 alpha-thio-SL. Similarly, preincubation of testicular microsomes with anti-P-45017 alpha,lyase IgG to inhibit 17 alpha-hydroxylation, diminished the subsequent loss of P-450 caused by 7 alpha-thio-SL. The results indicate that the 17 alpha-hydroxylase catalyzes the conversion of 7 alpha-thio-SL to the reactive metabolite responsible for P-450 destruction. The accompanying loss of 17 alpha-hydroxylase activity supports the hypothesis that suicide inhibition is the mechanism involved.
Kossor
D C
DC
Department of Pharmacology and Toxicology, Philadelphia College of Pharmacy and Science, PA 19104.
Kominami
S
S
Takemori
S
S
Colby
H D
HD
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004789:Enzyme Activation; D006168:Guinea Pigs; D007158:Immunologic Techniques; D008297:Male; D008861:Microsomes / Q000201:enzymology; D009249:NADP / Q000378:metabolism; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013737:Testis / Q000201:enzymology*
D013148:Spironolactone; C033554:7 alpha-thiospironolactone; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D013254:Steroid 17-alpha-Hydroxylase