ACETAMINOPHEN NEPHROTOXICITY IN THE CD-1 MOUSE .2. PROTECTION BY PROBENECID AND AT-125 WITHOUT DIMINUTION OF RENAL COVALENT BINDING

Acetaminophen (APAP) administration (600 mg/kg, ip) to 18-hr fasted, 3 -month-old male CD-1 mice results in necrosis of the convoluted renal proximal tubules with a corresponding elevation of plasma urea nitroge n (BUN). Administration of the gamma-glutamyl transpeptidase inhibitor , L-(alpha pha-amino-3-chloro-4,5-dihydroxy-5-isoxazoleacetic acid (AT -125) (50 mg/kg, ip), to mice 30 min before APAP significantly diminis hed the APAP-induced histopathologic damage and BUN elevation. Adminis tration of the organic-anion transport inhibitor, probenecid (150 mg/k g, ip), 30 min before APAP challenge also protected against the APAP-i nduced elevation of BUN and detectable histopathologic changes. By con trast, pretreatment of mice with the cysteine conjugate beta-lyase inh ibitor, (aminooxy)acetic acid (100 mg/kg, ip), 1 hr before APAP did no t alter nephrotoxicity. None of the pretreatments altered the APAP-ind uced elevation of plasma sorbitol dehydrogenase activity, nor were the re any detectable changes in liver histopathology after APAP challenge . Despite the protective effects of both probenecid and AT-125 against nephrotoxicity, they did not affect either the level of immunochemica lly detectable covalent binding to protein or the depletion of renal g lutathione at 4 hr after APAP. Thus, the protection appears independen t of effects on renal APAP uptake or activation and indirectly suggest s that an APAP-glutathione conjugate may contribute to the observed ne phrotoxicity. (C) 1996 Academic Press, Inc.