Galbraith R A, Drummond G S, Krey L, Kappas A
Pharmacology. 1987;34(5):241-9. doi: 10.1159/000138275.
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.
给成年雄性大鼠注射钴原卟啉会强烈诱导肝脏血红素加氧酶，导致肝脏中细胞色素P - 450含量显著下降以及相关的代谢异常，包括体重增加呈剂量依赖性减少，血清睾酮浓度显著下降，而血清促黄体生成素水平却没有代偿性升高。在单次皮下注射金属卟啉（25 μmol/kg体重）后，这些异常至少持续5 - 6周。对成对饲养的对照大鼠和经金属卟啉处理的大鼠进行的实验表明，钴原卟啉引起的雄激素功能障碍与该化合物导致的体重减轻没有因果关系。正如预期的那样，钴原卟啉显著诱导了肝脏血红素加氧酶活性；处理大鼠的下丘脑该酶活性未改变，但垂体总体中的酶活性升高（约5倍）。然而，尽管肝脏细胞色素P - 450含量预期会下降，但下丘脑和垂体中的细胞色素P - 450含量未发现变化。在实验中，钴原卟啉在肝脏中产生的增强的血红素加氧酶活性被该酶的竞争性抑制剂锡原卟啉完全拮抗，钴原卟啉产生的内分泌抑制和体重减轻均未改变。因此，这些现象显然与钴原卟啉对血红素加氧酶的作用无关。在这些实验中无法确定钴原卟啉是否通过中枢作用损害食欲和内分泌控制机制，但这仍然可能是这种合成血红素类似物新作用的一种解释。
