Acetaminophen nephrotoxicity in the CD-1 mouse. II. 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 nitrogen (BUN). Administration of the gamma-glutamyl transpeptidase inhibitor, L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydroxy- 5-isoxazoleacetic acid (AT-125) (50 mg/kg, ip), to mice 30 min before APAP significantly diminished the APAP-induced histopathologic damage and BUN elevation. Administration of the organic-anion transport inhibitor, probenecid (150 mg/kg, ip), 30 min before APAP challenge also protected against the APAP-induced elevation of BUN and detectable histopathologic changes. By contrast, pretreatment of mice with the cysteine conjugate beta-lyase inhibitor, (aminooxy)acetic acid (100 mg/kg, ip), 1 hr before APAP did not alter nephrotoxicity. None of the pretreatments altered the APAP-induced elevation of plasma sorbitol dehydrogenase activity, nor were there 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 immunochemically detectable covalent binding to protein or the depletion of renal glutathione at 4 hr after APAP. Thus, the protection appears independent of effects on renal APAP uptake or activation and indirectly suggests that an APAP-glutathione conjugate may contribute to the observed nephrotoxicity.
Emeigh Hart
S G
SG
Department of Pathobiology, University of Connecticut, Storrs 06029-2092, USA.
Wyand
D S
DS
Khairallah
E A
EA
Cohen
S D
SD
D000082:Acetaminophen / Q000008:administration & dosage / Q000633:toxicity*; D000625:Aminooxyacetic Acid / Q000008:administration & dosage / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001806:Blood Urea Nitrogen; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D017136:Ion Transport / Q000187:drug effects; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D011339:Probenecid / Q000008:administration & dosage / Q000494:pharmacology*; D012076:Renal Agents / Q000008:administration & dosage / Q000494:pharmacology*
D018712:Analgesics, Non-Narcotic; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D012076:Renal Agents; D000625:Aminooxyacetic Acid; D000082:Acetaminophen; D007064:L-Iditol 2-Dehydrogenase; D005978:Glutathione; C006303:acivicin; D011339:Probenecid