Schnellmann R G, Monks T J, Mandel L J, Lau S S
Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens 30602.
Toxicol Appl Pharmacol. 1989 Jun 1;99(1):19-27. doi: 10.1016/0041-008x(89)90107-5.
2-Bromohydroquinone (BHQ) is a model toxic hydroquinone and plays an important role in bromobenzene-induced nephrotoxicity. Proximal tubules isolated to contain decreased glutathione (GSH) levels were at least twice as sensitive to the GSH depleting effects of BHQ and BHQ-induced mitochondrial dysfunction as were tubules with "normal" (i.e., in vivo) GSH content. The decrease in tubular GSH content resulted from BHQ-GSH conjugate formation. A mono-GSH conjugate (2-bromo-3-(glutathion-S-yl)hydroquinone) and a di-GSH conjugate (2-bromo-3,5- or 6-(diglutathion-S-yl)hydroquinone) were identified. In addition, a glucuronide conjugate was identified (2-bromo-1- or 4-O-glucuronylhydroquinone). BHQ-GSH conjugates were not responsible for BHQ-induced toxicity since (1) tubules with normal levels of GSH were more resistant to BHQ-induced toxicity even though they formed more BHQ-GSH conjugates than tubules with decreased GSH levels and (2) inhibition of gamma-glutamyltranspeptidase did not prevent BHQ-induced toxicity. BHQ-equivalents bound covalently to tubular protein in a concentration-, time-, and temperature-dependent manner with the majority of the binding (61%) occurring during the first 15 min after exposure to 0.2 mM BHQ. Tubules pretreated with GSH underwent less BHQ-protein alkylation and mitochondrial dysfunction, and the amount of BHQ recovered and BHQ-di-GSH conjugate formed increased. These data suggest that BHQ is biotransformed to a reactive intermediate (2-bromoquinone and/or 2-bromosemiquinone) and that this intermediate can react with GSH to form BHQ-GSH conjugates and/or bind covalently to tubular protein which may result in mitochondrial dysfunction and tubular death.
2-溴对苯二酚（BHQ）是一种典型的毒性对苯二酚，在溴苯诱导的肾毒性中起重要作用。分离出的近端小管中谷胱甘肽（GSH）水平降低，其对BHQ消耗GSH的作用以及BHQ诱导的线粒体功能障碍的敏感性至少是具有“正常”（即体内）GSH含量的小管的两倍。小管中GSH含量的降低是由于BHQ-GSH共轭物的形成。鉴定出了一种单GSH共轭物（2-溴-3-（谷胱甘肽-S-基）对苯二酚）和一种双GSH共轭物（2-溴-3,5-或6-（二谷胱甘肽-S-基）对苯二酚）。此外，还鉴定出了一种葡糖醛酸共轭物（2-溴-1-或4-O-葡糖醛酸基对苯二酚）。BHQ-GSH共轭物与BHQ诱导的毒性无关，因为（1）GSH水平正常的小管对BHQ诱导的毒性更具抗性，尽管它们比GSH水平降低的小管形成更多的BHQ-GSH共轭物；（2）抑制γ-谷氨酰转肽酶并不能预防BHQ诱导的毒性。BHQ等效物以浓度、时间和温度依赖性方式与小管蛋白共价结合，大部分结合（61%）发生在暴露于0.2 mM BHQ后的前15分钟内。用GSH预处理的小管发生的BHQ-蛋白烷基化和线粒体功能障碍较少，回收的BHQ量和形成的BHQ-双GSH共轭物增加。这些数据表明，BHQ被生物转化为一种反应性中间体（2-溴醌和/或2-溴半醌），并且这种中间体可以与GSH反应形成BHQ-GSH共轭物和/或与小管蛋白共价结合，这可能导致线粒体功能障碍和小管死亡。
