Suppression of 5 alpha-androstane-3 beta,17 beta-diol hydroxylase activity in rat pituitary by cobalt protoporphyrin: implications for testosterone homeostasis.
Cobalt protoporphyrin (CoPP) administered subcutaneously to adult male rats caused a marked reduction in the conversion of 5 alpha-androstane-3 beta-17 beta-diol (3 beta-adiol) to its main triol derivative (6 alpha-atriol) by homogenates of the pituitary but not of the prostate or brain (ventromedial hypothalamus and cortex). No effect in the brain was observed when this heme analogue was infused intracerebroventricularly. 3 beta-adiol hydroxylase, the enzyme responsible for the reaction and whose main function is thought to be the elimination of dihydrotestosterone and its metabolites from target tissues, was also inhibited by CoPP and SKF-525A added in vitro. The reaction was microsomal and dependent on NADPH. It is proposed that the lack of reciprocal elevation of luteinizing hormone in the face of the low testosterone levels observed following treatment with CoPP may be due, in part, to increased levels of androstanediols. These metabolites accumulate because of increased production from testosterone and decreased conversion to their triol derivatives in the pituitary.
Jellinck
P H
PH
Department of Biochemistry, Queen's University, Kingston, Ontario, Canada.
Galbraith
R A
RA
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D006706:Homeostasis; D007031:Hypothalamus / Q000187:drug effects / Q000201:enzymology; D008297:Male; D010902:Pituitary Gland / Q000187:drug effects / Q000201:enzymology*; D011467:Prostate / Q000187:drug effects / Q000201:enzymology; D011524:Protoporphyrins / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D013739:Testosterone / Q000502:physiology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D011524:Protoporphyrins; D013739:Testosterone; C007095:cobaltiprotoporphyrin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases