Rossi L, Moore G A, Orrenius S, O'Brien P J
Arch Biochem Biophys. 1986 Nov 15;251(1):25-35. doi: 10.1016/0003-9861(86)90047-0.
The toxicity of quinones is believed to be mediated via redox cycling involving formation of semiquinone radicals which autoxidize to form active oxygen species. However, when the cytotoxicity of benzoquinones was compared using freshly isolated rat hepatocytes, benzoquinones which did not mediate oxidative stress were highly toxic. Thus, the benzoquinone analogs in decreasing order of cytotoxicity were 2-CH3-, 2-Br-, unsubstituted, 2,6-(CH3)2-, 2,5-(CH3)2-, and 2,3,5-(CH3)3-benzoquinone. Cellular thiols were rapidly depleted and glutathione (GSH) was converted to a quinone conjugate without oxidation to glutathione disulfide. No increase in cyanide-resistant respiration was observed and benzoquinone-induced cytotoxicity was not enhanced by inactivation of catalase or glutathione reductase. In contrast, duroquinone [2,3,5,6-(CH3)4-benzoquinone], which stimulated cyanide-resistant respiration and GSH oxidation, was only cytotoxic when catalase or glutathione reductase was inactivated. These results suggest that alkylation and/or oxidative stress may be important mechanisms in the cytotoxicity of benzoquinone derivatives.
醌类的毒性被认为是通过氧化还原循环介导的，该循环涉及半醌自由基的形成，半醌自由基自动氧化形成活性氧物种。然而，当使用新鲜分离的大鼠肝细胞比较苯醌的细胞毒性时，不介导氧化应激的苯醌具有高毒性。因此，细胞毒性由高到低的苯醌类似物依次为2-CH3-、2-Br-、未取代的、2,6-(CH3)2-、2,5-(CH3)2-和2,3,5-(CH3)3-苯醌。细胞硫醇迅速耗尽，谷胱甘肽（GSH）转化为醌结合物，而没有氧化为谷胱甘肽二硫化物。未观察到抗氰呼吸增加，过氧化氢酶或谷胱甘肽还原酶失活也不会增强苯醌诱导的细胞毒性。相反，刺激抗氰呼吸和GSH氧化的杜醌[2,3,5,6-(CH3)4-苯醌]只有在过氧化氢酶或谷胱甘肽还原酶失活时才具有细胞毒性。这些结果表明，烷基化和/或氧化应激可能是苯醌衍生物细胞毒性的重要机制。
