Trakshel G M, Sluss P M, Maines M D
Department of Biophysics, University of Rochester School of Medicine, New York 14642.
Pediatr Res. 1992 Feb;31(2):196-201. doi: 10.1203/00006450-199202000-00022.
Synthetic metalloporphyins inhibit formation of bilirubin by the heme oxygenase system, an ability that is of considerable experimental and clinical interest for suppression of jaundice in the newborn. The present investigation compares the consequences of treatment with Sn- and Zn-protoporphyrin on hemoprotein-dependent enzymes of the rat adrenals and corticosterone production and defines Sn-protoporphyrin as a potent toxin to adrenal functions. Treatment of rats with Sn-protoporphyrin (two doses of 50 mumols/kg, in 7 d) resulted in a marked reduction of 30-40% in cytochrome P-450-dependent adrenal microsomal 21 alpha-hydroxylase and mitochondrial 11 beta-hydroxylase activities. In the serum, the levels of corticosterone were reduced to about 70% of the control value. In addition, the mitochondrial cytochrome P-450SCC activity was decreased by about 50%. This decrease, however, could not be attributed to a reduced total heme level or an accelerated heme degradatory activity. Disruption by Sn-protoporphyrin of adrenal hemoprotein-dependent functions was not restricted to steroidogenic activities and encompassed drug metabolism activity of the organ; benzo(a)pyrene hydroxylase activity of both the microsomal and the mitochondrial fractions, as well as the microsomal NADPH-cytochrome P-450 reductase activity, were significantly reduced. Zn-protoporphyrin did not cause significant alterations in the above measured parameters although it too was effective in inhibiting the hepatic microsomal heme oxygenase activity. In light of the presently defined adverse effects of Sn-protoporphyrin on adrenal steroidogenesis, we suggest Zn-protoporphyrin is the agent of choice for potential use in treatment of hyperbilirubinemia in humans.
合成金属卟啉可抑制血红素加氧酶系统生成胆红素，该能力在抑制新生儿黄疸方面具有重大的实验和临床意义。本研究比较了用锡原卟啉和锌原卟啉治疗对大鼠肾上腺中依赖血红素蛋白的酶以及皮质酮生成的影响，并确定锡原卟啉是肾上腺功能的一种强效毒素。用锡原卟啉（两剂，每千克50微摩尔，共7天）治疗大鼠，导致细胞色素P - 450依赖的肾上腺微粒体21α - 羟化酶和线粒体11β - 羟化酶活性显著降低30 - 40%。在血清中，皮质酮水平降至对照值的约70%。此外，线粒体细胞色素P - 450SCC活性降低了约50%。然而，这种降低不能归因于总血红素水平的降低或血红素降解活性的加快。锡原卟啉对肾上腺依赖血红素蛋白功能的破坏并不局限于类固醇生成活性，还包括该器官的药物代谢活性；微粒体和线粒体部分的苯并(a)芘羟化酶活性以及微粒体NADPH - 细胞色素P - 450还原酶活性均显著降低。锌原卟啉虽然也能有效抑制肝微粒体血红素加氧酶活性，但并未引起上述测量参数的显著变化。鉴于目前已明确锡原卟啉对肾上腺类固醇生成的不良影响，我们建议锌原卟啉是可能用于治疗人类高胆红素血症的首选药物。
