Vile G, Winterbourn C
Department of Pathology, Christchurch School of Medicine, New Zealand.
Biochem Pharmacol. 1990 Feb 15;39(4):769-74. doi: 10.1016/0006-2952(90)90157-g.
Incubation of rabbit heart microsomes with Adriamycin and NADPH resulted in the oxidation of approximately 25% of protein thiols and 66% inhibition of Ca-ATPase activity. Thiol oxidation and Ca-ATPase inactivation were iron-dependent and could be catalysed by ferritin. Removal of contaminating catalase revealed that both processes required H2O2 which could be supplied by O2 under aerobic conditions. However, O2- was not involved. Butylated hydroxytoluene (BHT), alpha-tocopherol and beta-carotene inhibited lipid peroxidation of microsomes, but did not inhibit thiol oxidation or the inactivation of Ca-ATPase. Likewise, the hydroxyl radical scavengers benzoate, formate and mannitol were not inhibitory. Glutathione (GSH), however, prevented inactivation of Ca-ATPase. It is concluded that Adriamycin-enhanced redox reactions involving iron and H2O2 are responsible for oxidizing microsomal thiol groups and inhibition of Ca-ATPase. Disruption of Ca transport within the myocyte by this process could contribute to the cardiotoxicity of Adriamycin.
将兔心脏微粒体与阿霉素和烟酰胺腺嘌呤二核苷酸磷酸（NADPH）一起温育，导致约25%的蛋白质硫醇被氧化，且钙-ATP酶活性受到66%的抑制。硫醇氧化和钙-ATP酶失活依赖于铁，并且可由铁蛋白催化。去除污染的过氧化氢酶表明，这两个过程都需要过氧化氢，在有氧条件下，氧气可提供过氧化氢。然而，超氧阴离子（O2-）并不参与。丁基羟基甲苯（BHT）、α-生育酚和β-胡萝卜素抑制微粒体的脂质过氧化，但不抑制硫醇氧化或钙-ATP酶的失活。同样，羟基自由基清除剂苯甲酸、甲酸和甘露醇也没有抑制作用。然而，谷胱甘肽（GSH）可防止钙-ATP酶失活。得出的结论是，阿霉素增强的涉及铁和过氧化氢的氧化还原反应是微粒体硫醇基团氧化和钙-ATP酶抑制的原因。该过程导致心肌细胞内钙转运的破坏可能是阿霉素心脏毒性的原因。
