STUDIES ON THE EFFECTS OF L(ALPHA-S,5S)-ALPHA- AMINO-3-CHLORO-4,5-DIHYDRO-5-ISOXAZOLEACETIC ACID (AT-125) ON 4-AMINOPHENOL-INDUCED NEPHROTOXICITY IN THE FISCHER-344 RAT

4-Aminophenol (para-aminophenol; PAP) causes selective necrosis to the S-3 segment of the proximal tubule in experimental animals. The mechanism of PAP nephrotoxicity has not been fully elucidated, although it has been suggested to involve glutathione (GSH)-dependent S-conjugation followed by processing by the enzyme gamma-glutamyl transpeptidase (IFT) to the corresponding cysteine S-conjugate. This proposed toxicity mechanism was probed further by administering L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125), a potent gamma GT inhibitor, to Fischer 344 (F344) rats before treatment with PAP (100 mg/kg). AT-125 pretreatment did not appear to protect against PAP-induced nephrotoxicity as assessed by renal histopathology, clinical chemistry and proton nuclear magnetic resonance (H-1 NMR) spectroscopy of urine. These data suggest that renal gamma GT activity is not a prerequisite for PAP nephrotoxicity and that the generation of a cysteine S-conjugate is not a unique requirement for the induction of PAP nephrotoxicity.