The role of glutathione in p-aminophenol-induced nephrotoxicity in the mouse.
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.
Song
H
H
Department of Pharmacology and Toxicology, University of Louisville, School of Medicine, KY 40292, USA.
Lang
C A
CA
Chen
T S
TS
D000627:Aminophenols / Q000633:toxicity*; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000502:physiology*; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D010882:Piperonyl Butoxide / Q000494:pharmacology
D000627:Aminophenols; D007555:Isoxazoles; D019328:Buthionine Sulfoximine; D005978:Glutathione; D010882:Piperonyl Butoxide; C006303:acivicin; D001205:Ascorbic Acid; C026729:4-aminophenol