Hong S K, Anestis D K, Ball J G, Valentovic M A, Brown P I, Rankin G O
Department of Pharmacology, Marshall University School of Medicine, Huntington, West Virginia 25704-9388, USA.
Toxicol Appl Pharmacol. 1997 Nov;147(1):115-25. doi: 10.1006/taap.1997.8280.
A halogenated derivative of 4-aminophenol, 4-amino-2, 6-dichlorophenol (ADCP), is a potent nephrotoxicant and a weak hepatotoxicant in Fischer 344 rats. Although the mechanism of ADCP nephrotoxicity is unknown, ADCP could undergo oxidation to a reactive intermediate, such as a 4-amino-2,6-dichlorophenoxy radical or 2,6-dichloro-1,4-benzoquinoneimine, which can generate additional free radicals and/or covalently bind to cellular proteins. The toxic process might also be mediated by glutathione (GSH) conjugates of ADCP, as suggested for the mechanism of 4-aminophenol nephrotoxicity. In this study, the effects of modulators of oxidation and GSH conjugation-related metabolism or transport on ADCP-induced nephrotoxicity were examined. In one set of experiments, male Fischer 344 rats (four/group) were intraperitoneally (ip) administered ADCP (0.38 mmol/kg) only or coadministered an antioxidant, ascorbic acid (1.14 mmol/kg, ip) with ADCP. Administration of ascorbic acid markedly reduced both functional nephrotoxicity and morphological changes induced by ADCP. Administration of a gamma-glutamyltransferase (GGT) inhibitor, l-(alphaS, 5S)-alpha-amino-3-chloro-4,5-dihydroxy-5-isoxazoleacetic acid (10 mg/kg, ip), or a cysteine conjugate beta-lyase inhibitor, aminooxyacetic acid (0.5 mmol/kg, ip), 1 hr before ADCP (0.38 mmol/kg) challenge partially protected rats against ADCP nephrotoxicity. In contrast, administration of an organic anion transport inhibitor, probenecid (140 mg/kg, ip), 30 min before ADCP had little effect on ADCP nephrotoxicity. The GSH depletor, buthionine sulfoximine (890 mg/kg, ip), was given 2 hr prior to ADCP and only minimal protection was noted. In addition, the nonprotein sulfhydryl (NPSH) contents in renal cortex and liver were determined at 2 hr following the administration of ADCP only or ascorbic acid/ADCP. Ascorbic acid afforded complete prevention of the depletion of NPSH in the kidney and liver caused by ADCP administration and also prevented the elevation of renal glutathione disulfide content induced by ADCP. The results indicate that oxidation of ADCP appears to be essential to ADCP nephrotoxicity and that GSH or GSH-derived conjugates of ADCP may be partly responsible for the nephrotoxic effects of ADCP via a GGT-mediated mechanism.
4-氨基苯酚的卤代衍生物4-氨基-2,6-二氯苯酚（ADCP），在Fischer 344大鼠中是一种强效肾毒物和弱肝毒物。尽管ADCP肾毒性的机制尚不清楚，但ADCP可能会氧化成一种反应性中间体，如4-氨基-2,6-二氯苯氧基自由基或2,6-二氯-1,4-苯醌亚胺，它们可产生额外的自由基和/或与细胞蛋白质共价结合。毒性过程也可能由ADCP的谷胱甘肽（GSH）结合物介导，4-氨基苯酚肾毒性机制已有相关提示。在本研究中，检测了氧化和GSH结合相关代谢或转运调节剂对ADCP诱导的肾毒性的影响。在一组实验中，雄性Fischer 344大鼠（每组4只）仅腹腔注射（ip）ADCP（0.38 mmol/kg），或与抗氧化剂抗坏血酸（1.14 mmol/kg，ip）联合注射ADCP。抗坏血酸的给药显著降低了ADCP诱导的功能性肾毒性和形态学变化。在注射ADCP（0.38 mmol/kg）前1小时，腹腔注射γ-谷氨酰转移酶（GGT）抑制剂l-(αS,5S)-α-氨基-3-氯-4,5-二羟基-5-异恶唑乙酸（10 mg/kg）或半胱氨酸结合β-裂解酶抑制剂氨氧基乙酸（0.5 mmol/kg），可部分保护大鼠免受ADCP肾毒性。相反，在注射ADCP前30分钟腹腔注射有机阴离子转运抑制剂丙磺舒（140 mg/kg），对ADCP肾毒性几乎没有影响。在注射ADCP前2小时给予GSH耗竭剂丁硫氨酸亚砜胺（890 mg/kg，ip），仅观察到最小程度的保护作用。此外，在仅注射ADCP或抗坏血酸/ADCP后2小时，测定肾皮质和肝脏中的非蛋白巯基（NPSH）含量。抗坏血酸完全预防了ADCP给药引起的肾脏和肝脏中NPSH的消耗，也预防了ADCP诱导的肾谷胱甘肽二硫化物含量的升高。结果表明，ADCP的氧化似乎对ADCP肾毒性至关重要，并且ADCP的GSH或GSH衍生结合物可能通过GGT介导的机制部分导致ADCP的肾毒性作用。
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