Sokolove P M, Kester M B, Haynes J
Department of Pharmacology & Experimental Therapeutics, University of Maryland Medical School, Baltimore 21201.
Biochem Pharmacol. 1993 Aug 17;46(4):691-7. doi: 10.1016/0006-2952(93)90556-c.
Adriamycin (AdM) aglycones have dramatic effects on isolated heart mitochondria, oxidizing pyridine nucleotides, modifying sulfhydryl groups, and triggering a permeability transition of the inner membrane that results in free passage of solutes smaller than 1500 Da. In this investigation, the role of glutathione (GSH) peroxidase in these actions of the aglycones was evaluated, by comparing mitochondria from selenium-deficient and selenium-supplemented rats, with the following results. Selenium deficiency was without effect on the permeability transition of heart mitochondria, followed via Ca2+ release and triggered by AdM aglycone or by t-butyl hydroperoxide (TBH) or H2O2, both of which are authentic substrates of the peroxidase. The permeability transition of liver mitochondria was delayed by selenium deficiency regardless of the triggering agent; however, substantial triggering by the aglycone and TBH persisted in mitochondria from selenium-deficient animals. Selenium deficiency inhibited thiol modification elicited by AdM aglycone and H2O2 in heart mitochondria and by the aglycone, TBH, and possibly H2O2 in liver mitochondria. It would thus appear that AdM aglycone, TBH, and H2O2 can induce the permeability transition of isolated heart mitochondria via a process (or processes) distinct from the catalytic activity of the peroxidase. Furthermore, even in liver, where involvement of the peroxidase is observed, mechanisms other than the GSH cycle can contribute to transition induction by the aglycone and by TBH. Finally, mitochondrial-SH group modification by the aglycones appeared not to be causally linked to induction of the permeability transition. This laboratory has suggested that the effects of aglycone metabolites of AdM on mitochondria mediate the cardiotoxicity that limits use of the parent drug. The data presented in this paper argue against the involvement of GSH peroxidase in that process. They are in agreement with in vivo studies, which have generally failed to find evidence for amelioration of AdM cardiotoxicity in selenium-deficient animals.
阿霉素（AdM）糖苷配基对分离的心脏线粒体有显著影响，能氧化吡啶核苷酸、修饰巯基，并引发内膜通透性转变，导致分子量小于1500道尔顿的溶质自由通过。在本研究中，通过比较缺硒和补硒大鼠的线粒体，评估了谷胱甘肽（GSH）过氧化物酶在这些糖苷配基作用中的角色，结果如下。缺硒对心脏线粒体的通透性转变没有影响，该通透性转变通过Ca2+释放来跟踪，由AdM糖苷配基或叔丁基过氧化氢（TBH）或H2O2引发，后两者都是过氧化物酶的真正底物。无论触发剂是什么，缺硒都会延迟肝脏线粒体的通透性转变；然而，缺硒动物的线粒体中，糖苷配基和TBH仍能引发显著的通透性转变。缺硒抑制了AdM糖苷配基和H2O2在心脏线粒体中以及糖苷配基、TBH可能还有H2O2在肝脏线粒体中引起的巯基修饰。因此，似乎AdM糖苷配基、TBH和H2O2可通过不同于过氧化物酶催化活性的一个或多个过程诱导分离的心脏线粒体的通透性转变。此外，即使在观察到过氧化物酶参与的肝脏中，除GSH循环外的其他机制也可能导致糖苷配基和TBH诱导通透性转变。最后，糖苷配基对线粒体-SH基团的修饰似乎与通透性转变的诱导没有因果关系。本实验室曾提出，AdM糖苷配基代谢产物对线粒体的影响介导了限制母体药物使用的心脏毒性。本文给出的数据表明GSH过氧化物酶不参与该过程。它们与体内研究结果一致，体内研究通常未能找到缺硒动物中阿霉素心脏毒性得到改善的证据。
