Krueger B A, Trakshel G M, Sluss P M, Maines M D
Department of Biophysics, University of Rochester School of Medicine, New York 14642.
Endocrinology. 1991 Nov;129(5):2647-54. doi: 10.1210/endo-129-5-2647.
The toxic side-effects of the immunosuppressive drug cyclosporin (CsA) include testicular dysfunction and a decline in circulating testosterone. However, mechanisms for the consistently observed CsA-mediated depression of serum testosterone levels are unclear because of conflicting reports concerning circulating gonadotropin levels and incomplete studies of intratesticular steroidogenesis. To elucidate these mechanisms, endocrine-regulated testicular steroidogenesis and heme metabolic parameters were studied in male rats given sc injections of either 25 or 40 mg/kg.day CsA for 6 days and then killed on the seventh day. Consistent with earlier reports, CsA treatment dramatically suppressed serum testosterone levels (less than 20% of control at both CsA doses). Additionally, the intratesticular testosterone content declined with the higher CsA dose. Serum LH and FSH levels were elevated up to 2- to 4-fold after the higher CsA treatment regimen. Measurement of decreases in testicular receptors for LH revealed for the first time that CsA treatment significantly reduced the ability of the testes to respond to normal or elevated circulating levels of LH. In animals receiving higher dose of the drug, cytochrome P-450-dependent mitochondrial cholesterol side-chain cleavage activity, which is the rate-limiting step in steroidogenesis, was markedly reduced to a mere 30% of the control value. Additionally, the activity of the microsomal cytochrome P-450-dependent 17 alpha-hydroxylase was decreased to less than half of the control value. Biotransformation of the prototype drug, benzo(a)pyrene, as well as microsomal cytochrome P450 levels declined significantly after the higher CsA dose, suggesting that CsA has an adverse affect on testicular cytochromes P-450 in general. In addition, CsA treatment altered heme metabolic parameters; significant increases in the activity of uroporphyrinogen-I synthetase and total porphyrin content were noted. Conversely, the activity of ferrochelatase, the enzyme that incorporates iron into porphyrin to form heme molecule, decreased significantly, as did the total heme levels. The latter was reduced to only 61% of control values. The findings suggest the likelihood that the observed inhibition of heme formation may contribute substantially to the reduced levels of microsomal cytochromes P-450 and steroidogenic activities that depend on them. Taken collectively, these data suggest a plausible mechanism by which CsA may induce testicular dysfunction; as the result of a combination of reduction in the number of LH receptors and a suppression of heme formation, the hemoprotein-dependent steroidogenic enzymes activities are compromised, leading to an impairment of normal testicular function.
免疫抑制药物环孢素（CsA）的毒副作用包括睾丸功能障碍和循环睾酮水平下降。然而，由于关于循环促性腺激素水平的报道相互矛盾，且对睾丸内类固醇生成的研究不完整，因此一直观察到的CsA介导的血清睾酮水平降低的机制尚不清楚。为了阐明这些机制，我们对雄性大鼠进行了研究，这些大鼠皮下注射25或40mg/kg·天的CsA，持续6天，然后在第7天处死，研究了内分泌调节的睾丸类固醇生成和血红素代谢参数。与早期报道一致，CsA治疗显著抑制了血清睾酮水平（两种CsA剂量下均低于对照组的20%）。此外，较高CsA剂量下睾丸内睾酮含量下降。较高的CsA治疗方案后，血清LH和FSH水平升高至2至4倍。对LH睾丸受体减少的测量首次表明，CsA治疗显著降低了睾丸对正常或升高的循环LH水平作出反应的能力。在接受较高剂量药物的动物中，细胞色素P-450依赖性线粒体胆固醇侧链裂解活性（类固醇生成的限速步骤）显著降低至仅为对照值的30%。此外，微粒体细胞色素P-450依赖性17α-羟化酶的活性降低至对照值的一半以下。较高CsA剂量后，原型药物苯并(a)芘的生物转化以及微粒体细胞色素P450水平显著下降，这表明CsA总体上对睾丸细胞色素P-450有不良影响。此外，CsA治疗改变了血红素代谢参数；尿卟啉原-I合成酶活性和总卟啉含量显著增加。相反，将铁掺入卟啉以形成血红素分子的酶——亚铁螯合酶的活性显著降低，总血红素水平也显著降低。后者降至仅为对照值的61%。这些发现表明，观察到的血红素形成抑制可能在很大程度上导致了微粒体细胞色素P-450水平和依赖于它们的类固醇生成活性的降低。综合来看，这些数据表明了一种CsA可能诱导睾丸功能障碍的合理机制；由于LH受体数量减少和血红素形成受到抑制的共同作用，依赖血红素蛋白的类固醇生成酶活性受到损害，导致正常睾丸功能受损。
