Monks T J, Lau S S, Highet R J, Gillette J R
Drug Metab Dispos. 1985 Sep-Oct;13(5):553-9.
Incubation of either o-bromophenol or 2-bromohydroquinone with rat liver microsomes and 0.25 mM 35S-glutathione (GSH) gave rise to several isomeric 35S-GSH conjugates. A mixture of these isomeric GSH conjugates was prepared chemically and two were purified by HPLC; 1H-NMR spectroscopy revealed that one was 2-bromo-3-(glutathion-S-yl)hydroquinone and the other was a disubstituted GSH conjugate which could be either 2-bromo-3,5-(diglutathion-S-yl)hydroquinone or 2-bromo-3,6-(diglutathion-S-yl)hydroquinone. Injection of the disubstituted GSH conjugate intravenously to rats caused substantial elevations in blood urea nitrogen levels. Treatment of rats with AT-125 (Acivicin; NSC 163501; 10 mg/kg ip) caused a substantial inhibition of kidney gamma-glutamyl transpeptidase activity and decreased 2-bromohydroquinone-mediated elevations in blood urea nitrogen. These findings are consistent with the view that the kidney necrosis observed after administration of either bromobenzene (1), o-bromophenol (2), or 2-bromohydroquinone (3) might be due in part to 2-bromohydroquinone GSH conjugates formed in the liver and subsequently transported to the kidney and converted to ultimate nephrotoxic metabolite(s).
将邻溴苯酚或2-溴对苯二酚与大鼠肝微粒体以及0.25 mM的35S-谷胱甘肽（GSH）一起温育，会产生几种异构的35S-GSH缀合物。通过化学方法制备了这些异构GSH缀合物的混合物，并通过高效液相色谱法纯化了其中两种；1H-核磁共振光谱显示一种是2-溴-3-（谷胱甘肽-S-基）对苯二酚，另一种是二取代的GSH缀合物，可能是2-溴-3,5-（二谷胱甘肽-S-基）对苯二酚或2-溴-3,6-（二谷胱甘肽-S-基）对苯二酚。将二取代的GSH缀合物静脉注射给大鼠会导致血尿素氮水平大幅升高。用AT-125（阿西维辛；NSC 163501；10 mg/kg腹腔注射）处理大鼠会导致肾脏γ-谷氨酰转肽酶活性大幅抑制，并降低2-溴对苯二酚介导的血尿素氮升高。这些发现与以下观点一致，即给予溴苯（1）、邻溴苯酚（2）或2-溴对苯二酚（3）后观察到的肾脏坏死可能部分归因于在肝脏中形成的2-溴对苯二酚GSH缀合物，随后转运至肾脏并转化为最终的肾毒性代谢物。
