Rivera M I, Hinojosa L M, Hill B A, Lau S S, Monks T J
Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin 78712.
Drug Metab Dispos. 1994 Jul-Aug;22(4):503-10.
2-Br-(diglutathion-S-yl)hydroquinone (2-Br-(diGSyl)HQ) is a potent nephrotoxicant, causing glucosuria, enzymuria, proteinuria, elevations in blood urea nitrogen, and severe histological alterations to renal proximal tubules at doses of 10-15 mumol/kg. In contrast, 2-Br-3-(glutathion-S-yl)hydroquinone (2-Br-3-(GSyl)HQ) is substantially less nephrotoxic than 2-Br-(diGSyl)HQ and requires a dose of at least 50 mumol/kg to cause modest elevations in blood urea nitrogen concentrations. The reason or reasons for this difference in potency is unclear, but since inhibition of renal gamma-glutamyl transpeptidase (gamma-GT) prevents 2-Br-(diGSyl)HQ-mediated nephrotoxicity, metabolism of these conjugates by the kidney must play an important role. To address this question we have compared the metabolism and toxicity of 2-Br-(diGSyl)HQ and 2-Br-3-(GSyl)HQ in the in situ perfused rat kidney (ISPRK). Following infusion of 20 mumol 2-Br-3-(GSyl)HQ into the right renal artery of male Sprague Dawley rats, a total of 23.5 +/- 1.9% (mean +/- SE) of the dose was accounted for in urine and bile over a period of 180 min. 2-Bromo-3-(cystein-S-yl)hydroquinone and 2-bromo-3-(N-acetylcystein-S-yl)hydroquinone were identified in urine, and unchanged 2-Br-3-(GSyl)HQ was identified in urine and bile. The product arising from the oxidative cyclization of 2-bromo-3-(cystein-S-glycine)hydroquinone, 2H-(3-glycine)-7-hydroxy-8-bromo-1,4-benzothiazine, was also identified in urine.(ABSTRACT TRUNCATED AT 250 WORDS)
2-溴-（二谷胱甘肽-S-基）对苯二酚（2-Br-（二GSyl）HQ）是一种强效肾毒物，在剂量为10 - 15 μmol/kg时可导致糖尿、酶尿、蛋白尿、血尿素氮升高以及肾近端小管严重的组织学改变。相比之下，2-溴-3-（谷胱甘肽-S-基）对苯二酚（2-Br-3-（GSyl）HQ）的肾毒性远低于2-Br-（二GSyl）HQ，且至少需要50 μmol/kg的剂量才能使血尿素氮浓度适度升高。这种效力差异的原因尚不清楚，但由于抑制肾γ-谷氨酰转肽酶（γ-GT）可预防2-Br-（二GSyl）HQ介导的肾毒性，因此肾脏对这些共轭物的代谢必定起着重要作用。为解决这个问题，我们比较了2-Br-（二GSyl）HQ和2-Br-3-（GSyl）HQ在原位灌注大鼠肾脏（ISPRK）中的代谢和毒性。将20 μmol 2-Br-3-（GSyl）HQ注入雄性Sprague Dawley大鼠的右肾动脉后，在180分钟内，尿液和胆汁中总共占该剂量的23.5±1.9%（平均值±标准误）。尿液中鉴定出2-溴-3-（半胱氨酸-S-基）对苯二酚和2-溴-3-（N-乙酰半胱氨酸-S-基）对苯二酚，尿液和胆汁中鉴定出未变化的2-Br-3-（GSyl）HQ。尿液中还鉴定出了由2-溴-3-（半胱氨酸-S-甘氨酸）对苯二酚氧化环化产生的产物2H-（3-甘氨酸）-7-羟基-8-溴-1,4-苯并噻嗪。（摘要截断于250字）
