Lupp A, Kuhn U D, Karge E, Adam G, Fleck C
Institute of Pharmacology and Toxicology, Friedrich Schiller University, 07740 Jena, Germany.
Int J Clin Pharmacol Ther. 2006 May;44(5):225-32. doi: 10.5414/cpp44225.
The use of cyclosporin A (CSA) and tacrolimus (TAC) in organ transplantation and in the therapy of immune disorders is often hampered by adverse effects, mainly nephro-, hepato- and neurotoxicity. For the development of these side effects, among others, an increased formation of reactive oxygen species, probably generated by the cytochrome P450 (CYP) system, has been accused. Since in this respect literature data are inconsistent, in the present study possible pro- and/or antioxidant effects of CSA and TAC and the involvement of the CYP system were re-evaluated in vitro.
Effects of CSA and TAC were examined on CYP mediated oxidase functions by stimulated lipid peroxidation (LPO), H2O2 production, and lucigenin (LC) or luminol (LM) amplified chemiluminescence (CL) in liver microsomes of either untreated rats or of rats treated with beta-naphthoflavone (BNF), phenobarbital (PB) or dexamethasone (DEX) and in human liver microsomes.
In rat liver microsomes, CSA displayed pro-oxidant properties (though only very slightly), whereas in human liver microsomes small antioxidant effects were seen. With TAC in both species the antioxidant capacity prevailed. Treatment of rats with BNF or DEX caused an increase in the pro-oxidant effects of CSA with respect to LPO or LM-CL, whereas in liver microsomes of DEX-treated rats H2O2 production and LC-CL were diminished.
CSA seems to have both pro-oxidant and antioxidant properties, whereas with TAC mainly an antioxidant capacity was seen. The CYP system seems to be involved in the pro-oxidant influence of CSA. Whether pro-oxidant or antioxidant effects predominate may depend on the antioxidant capacity of a tissue and on the CYP isoforms mainly present.
环孢素A（CSA）和他克莫司（TAC）在器官移植及免疫疾病治疗中的应用常因不良反应而受限，主要不良反应包括肾毒性、肝毒性和神经毒性。在这些副作用的发生过程中，有人指责细胞色素P450（CYP）系统可能导致活性氧生成增加。由于这方面的文献数据并不一致，本研究在体外重新评估了CSA和TAC可能的促氧化和/或抗氧化作用以及CYP系统的参与情况。
通过刺激脂质过氧化（LPO）、过氧化氢（H2O2）生成以及光泽精（LC）或鲁米诺（LM）增强的化学发光（CL），检测CSA和TAC对未处理大鼠或用β-萘黄酮（BNF）、苯巴比妥（PB）或地塞米松（DEX）处理的大鼠肝脏微粒体以及人肝脏微粒体中CYP介导的氧化酶功能的影响。
在大鼠肝脏微粒体中，CSA表现出促氧化特性（尽管非常轻微），而在人肝脏微粒体中则观察到较小的抗氧化作用。在两种物种中，TAC均以抗氧化能力为主。用BNF或DEX处理大鼠会导致CSA对LPO或LM-CL的促氧化作用增强，而在DEX处理的大鼠肝脏微粒体中，H2O2生成和LC-CL减少。
CSA似乎同时具有促氧化和抗氧化特性，而TAC主要表现出抗氧化能力。CYP系统似乎参与了CSA的促氧化影响。促氧化或抗氧化作用何者占主导可能取决于组织的抗氧化能力以及主要存在的CYP同工酶。
