Klos C, Koob M, Kramer C, Dekant W
Institut für Toxikologie, Universität Würzburg, Germany.
Toxicol Appl Pharmacol. 1992 Jul;115(1):98-106. doi: 10.1016/0041-008x(92)90372-y.
p-Aminophenol causes necrosis of the pars recta of the proximal tubules in rats, and its nephrotoxicity may be due to glutathione-dependent bioactivation reactions. We have investigated the hepatic metabolism of p-aminophenol in Wistar rats and the cytotoxicity of formed glutathione S-conjugates in rat renal epithelial cells. After ip application of p-aminophenol (100 mg/kg), the following metabolites were identified in rat bile: 4-amino-2-(glutathion-S-yl)phenol, 4-amino-3-(glutathion-S-yl)-phenol, 4-amino-2,5-bis(glutathion-S-yl)phenol, 4-amino-2,3,5(or 6)-tris(glutathion-S-yl)phenol, an aminophenol conjugate (likely a sulfate or glucuronide), acetaminophen glucuronide, and 3-(glutathion-S-yl)acetaminophen. 4-Amino-3-(glutathion-S-yl)phenol, 4-amino-2,5-bis(glutathion-S-yl)phenol, and 4-amino-2,3,5(or 6)-tris(glutathion-S-yl)phenol induced a dose- and time-dependent loss of cell viability in rat kidney cortical cells. Cell killing was significantly reduced by inhibition of gamma-glutamyl transpeptidase with Acivicin. p-Aminophenol was also toxic to renal epithelial cells. Coincubation of p-aminophenol with tetraethylammonium bromide, a competitive inhibitor of the organic cation transporter, and with SKF-525A, an inhibitor of cytochrome P450, protected cells from p-aminophenol-induced toxicity. p-Aminophenol would thus be accumulated in the kidney mainly by organic cation transport systems, which are concentrated in the S-1 segment of the proximal tubule. However, p-aminophenol toxicity in vivo is directed toward the S-2 and S-3 segments, which are rich in gamma-glutamyl transpeptidase. These results and the observation that biliary cannulation and glutathione depletion reduce p-aminophenol nephrotoxicity suggest that the biosynthesis of toxic glutathione conjugates is responsible for p-aminophenol nephrotoxicity in vivo. The aminophenol glutathione S-conjugates formed induce p-aminophenol nephrotoxicity by a pathway dependent on gamma-glutamyl transpeptidase.
对氨基苯酚可导致大鼠近端肾小管直部坏死，其肾毒性可能归因于谷胱甘肽依赖性生物活化反应。我们研究了对氨基苯酚在Wistar大鼠体内的肝脏代谢以及所形成的谷胱甘肽S - 共轭物对大鼠肾上皮细胞的细胞毒性。腹腔注射对氨基苯酚（100 mg/kg）后，在大鼠胆汁中鉴定出以下代谢产物：4 - 氨基 - 2 -（谷胱甘肽 - S - 基）苯酚、4 - 氨基 - 3 -（谷胱甘肽 - S - 基）苯酚、4 - 氨基 - 2,5 - 双（谷胱甘肽 - S - 基）苯酚、4 - 氨基 - 2,3,5（或6） - 三（谷胱甘肽 - S - 基）苯酚、一种氨基酚共轭物（可能是硫酸盐或葡糖醛酸酯）、对乙酰氨基酚葡糖醛酸酯和3 -（谷胱甘肽 - S - 基）对乙酰氨基酚。4 - 氨基 - 3 -（谷胱甘肽 - S - 基）苯酚、4 - 氨基 - 2,5 - 双（谷胱甘肽 - S - 基）苯酚和4 - 氨基 - 2,3,5（或6） - 三（谷胱甘肽 - S - 基）苯酚在大鼠肾皮质细胞中诱导了剂量和时间依赖性的细胞活力丧失。用阿西维辛抑制γ - 谷氨酰转肽酶可显著降低细胞杀伤作用。对氨基苯酚对肾上皮细胞也有毒性。将对氨基苯酚与有机阳离子转运体的竞争性抑制剂溴化四乙铵以及细胞色素P450抑制剂SKF - 525A共同孵育，可保护细胞免受对氨基苯酚诱导的毒性。因此，对氨基苯酚主要通过集中在近端小管S - 1段的有机阳离子转运系统在肾脏中蓄积。然而，对氨基苯酚在体内的毒性作用主要针对富含γ - 谷氨酰转肽酶的S - 2和S - 3段。这些结果以及胆管插管和谷胱甘肽耗竭可降低对氨基苯酚肾毒性的观察结果表明，有毒谷胱甘肽共轭物的生物合成是对氨基苯酚在体内肾毒性的原因。所形成的氨基酚谷胱甘肽S - 共轭物通过依赖γ - 谷氨酰转肽酶的途径诱导对氨基苯酚肾毒性。
