Song H, Lang C A, Chen T S
Department of Pharmacology and Toxicology, University of Louisville, School of Medicine, KY 40292, USA.
Drug Chem Toxicol. 1999 Aug;22(3):529-44. doi: 10.3109/01480549909042530.
p-Aminophenol (PAP) produces nephrotoxicity in rats through a mechanism presumably involving oxidation and conjugation with glutathione (GSH). Recently it was found that PAP also causes nephrotoxicity in mice as evidenced by elevated blood urea nitrogen (BUN) and serum creatinine levels. The objective of this study was to further investigate the mechanism and elucidate the role of GSH in PAP-induced nephrotoxicity in the mouse. Male C57BL/6 mice injected i.p. with various doses of PAP were sacrificed at 12 hr for measurement of BUN and serum creatinine levels and determination of the extent of renal cortical nonprotein sulfhydryl (NPSH) and GSH depletion. PAP depleted renal cortical NPSH content in a dose- and time-dependent manner. Depletion of NPSH in mouse kidney did not occur at PAP doses below 600 mg/kg. Buthionine sulfoximine, an inhibitor of GSH synthesis, decreased nephrotoxicity. Ascorbate, a reducing agent, prevented PAP-induced nephrotoxicity and attenuated renal cortical NPSH depletion. However, acivicin and aminooxyacetic acid, inhibitors of gamma-glutamyltranspeptidase and beta-lyase, respectively, did not prevent toxicity in the mouse. Piperonyl butoxide, an inhibitor of cytochrome P-450 enzymes, enhanced nephrotoxicity and renal cysteine depletion but not GSH depletion. The results suggest that PAP-induced nephrotoxicity in the mouse may involve oxidation and formation of a GSH conjugate.
对氨基苯酚（PAP）通过一种可能涉及氧化以及与谷胱甘肽（GSH）结合的机制在大鼠中产生肾毒性。最近发现，PAP在小鼠中也会导致肾毒性，血尿素氮（BUN）和血清肌酐水平升高就是证据。本研究的目的是进一步探究该机制，并阐明GSH在PAP诱导的小鼠肾毒性中的作用。腹腔注射不同剂量PAP的雄性C57BL/6小鼠在12小时后被处死，以测量BUN和血清肌酐水平，并测定肾皮质非蛋白巯基（NPSH）和GSH消耗的程度。PAP以剂量和时间依赖性方式消耗肾皮质NPSH含量。在PAP剂量低于600 mg/kg时，小鼠肾脏中未发生NPSH消耗。丁硫氨酸亚砜胺，一种GSH合成抑制剂，可降低肾毒性。抗坏血酸，一种还原剂，可预防PAP诱导的肾毒性并减轻肾皮质NPSH消耗。然而，阿西维辛和氨基氧乙酸，分别为γ-谷氨酰转肽酶和β-裂解酶的抑制剂，并未预防小鼠的毒性。胡椒基丁醚，一种细胞色素P-450酶抑制剂，增强了肾毒性和肾半胱氨酸消耗，但未增强GSH消耗。结果表明，PAP诱导的小鼠肾毒性可能涉及氧化以及GSH共轭物的形成。
