Relationship of suppression of the androgenic axis by cobalt-protoporphyrin to its effects on weight loss and hepatic heme oxygenase induction.
Cobalt-protoporphyrin administration to adult male rats results in an intense induction of hepatic heme oxygenase, a pronounced decline of cytochrome P-450 content in liver and associated metabolic abnormalities, including a dose-dependent decrease in weight gain and a marked decline in serum concentrations of testosterone without a compensatory increase in serum luteinizing hormone levels. These abnormalities persist for at least 5-6 weeks after a single subcutaneous dose of the metalloporphyrin (25 mumol/kg b.w.). Experiments with pair-fed control and metalloporphyrin-treated rats indicated that the androgenic dysfunction produced by cobalt-protoporphyrin is not causally related to the associated weight loss produced by the compound. Hepatic heme oxygenase activity was markedly induced by cobalt-protoporphyrin as expected; the enzyme activity was not altered in hypothalami of treated rats but was elevated (approximately 5-fold) in pooled pituitaries. However, despite the expected decrease in hepatic cytochrome P-450 content, no changes were noted in cytochrome P-450 content of hypothalami or pituitaries. In experiments in which the enhanced heme oxygenase activity produced in liver by cobalt-protoporphyrin was completely antagonized by tin-protoporphyrin, a competitive inhibitor of the enzyme, neither the endocrine suppression nor the weight loss produced by cobalt-protoporphyrin was altered. These phenomena were thus clearly dissociated from the effects of cobalt-protoporphyrin on heme oxygenase. Whether or not cobalt-protoporphyrin acts centrally to impair both appetite and endocrine control mechanisms could not be determined in these experiments, but remains a possible explanation of the novel actions of this synthetic heme analogue.
D000728:Androgens / Q000502:physiology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D003864:Depression, Chemical; D004790:Enzyme Induction / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008665:Metalloporphyrins; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D011166:Porphyrins / Q000494:pharmacology*; D011524:Protoporphyrins / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013739:Testosterone / Q000097:blood
D000728:Androgens; D008665:Metalloporphyrins; D011166:Porphyrins; D011524:Protoporphyrins; D013739:Testosterone; C007095:cobaltiprotoporphyrin; C032628:tin protoporphyrin IX; D006899:Mixed Function Oxygenases; D006419:Heme Oxygenase (Decyclizing)