Inhibition of glutathione-related enzymes and cytotoxicity of ethacrynic acid and cyclosporine.
Inhibition of glutathione-related enzymes and cytotoxicity of ethacrynic acid and cyclosporine.
复制标题
抑制谷胱甘肽相关酶以及依他尼酸和环孢菌素的细胞毒性。
DOI：
10.1016/0006-2952(94)00474-z
复制
发表时间：
1995
影响因子：
5.8
通讯作者：
Rybak,LP
中科院分区：
文献类型：
--
作者：
Hoffman,DW;Wiebkin,P;Rybak,LP
谷胱甘肽（GSH）是一种内源性巯基，可对中间代谢和药物解毒过程中形成的活性氧和活性物质进行解毒。测试了具有一系列潜在毒性的化合物影响GSH还原酶和GSH S-转移酶活性的能力，这两种还原酶和GSH S-转移酶活性是GSH参与的两种主要解毒途径的每种组分。对测定氧化型和还原型GSH的高效液相色谱法进行了改进，使之适用于测定GSH还原酶活性。用这种方法，它是可能的，证明依他尼酸，抑制谷胱甘肽S-转移酶，也抑制谷胱甘肽还原酶的活性。依他尼酸对GSH还原酶的抑制作用与卡莫司汀（BCNU）相似。GSH还原酶活性不受顺式或反式铂、丁硫氨磺酰亚胺、其他髓袢利尿剂、环孢素A或氨基糖苷类药物的影响。环孢素在50 μM及更高浓度下抑制GSH S-转移酶。这些结果支持GSH介导的解毒机制在依他尼酸和环孢素相关的细胞毒性中的作用，这可能介导它们的毒性和它们在抗肿瘤治疗中作为抗肿瘤剂的潜力。更好地了解其毒性机制可以大大扩展这些药物的临床用途，因为这种毒性是其治疗和抗治疗作用的基础。
Glutathione (GSH) is an endogenous thiol that detoxifies active oxygen and reactive species formed during intermediary metabolism and drug detoxification. Compounds with a range of potential toxicities were; tested for their abilities to affect GSH reductase and GSH S-transferase activities, which are each components of the two principal detoxification pathways in which GSH participates. A high performance liquid chromatographic method for determining oxidized and reduced GSH was modified to assay GSH reductase activity. With this method it was possible to demonstrate that ethacrynic acid, which inhibits GSH S-transferase, also inhibits the activity of GSH reductase. Inhibition of GSH reductase by ethacrynic acid was similar to that seen with carmustine (BCNU). GSH reductase activity was not affected by cis- or transplatin, buthionine sulfoximine, other loop diuretics, cyclosporine A or aminoglycosides. Cyclosporine inhibited GSH S-transferase at 50 μM and higher concentrations. These results support a role for GSH-mediated detoxification mechanisms in ethacrynic acid- and cyclosporine-associated cytotoxicity, which may mediate their toxicities and their potential as adjunctive agents in antineoplastic therapy. A better understanding of the mechanism of their toxicity can greatly extend the clinical usefulness of these agents, as this toxicity is the basis of both their therapeutic and antitherapeutic actions.