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.