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p-aminophenol nephrotoxicity: biosynthesis of toxic glutathione conjugates.

Abstract
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.
AuthorsC Klos, M Koob, C Kramer, W Dekant
JournalToxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 115 Issue 1 Pg. 98-106 (Jul 1992) ISSN: 0041-008X [Print] United States
PMID1631900 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Aminophenols
  • Glutathione
  • 4-aminophenol
Topics
  • Aminophenols (metabolism, toxicity)
  • Animals
  • Bile (metabolism)
  • Cell Survival (drug effects)
  • Cells, Cultured
  • Chromatography, High Pressure Liquid
  • Epithelial Cells
  • Epithelium (drug effects)
  • Glutathione (biosynthesis, chemistry)
  • Hydrogen-Ion Concentration
  • Kidney (cytology, drug effects)
  • Liver (metabolism)
  • Male
  • Mass Spectrometry
  • Rats
  • Rats, Inbred Strains

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