Authors
Etemadi, Y., Fields, T. A., Ramachandran, A., Jaeschke, H.
Abstract
Acetaminophen (APAP) overdose is the leading cause of acute liver failure and is frequently complicated by acute kidney injury (AKI), which worsens clinical outcomes. Although N-acetylcysteine (NAC) effectively attenuates APAP-induced hepatotoxicity by restoring hepatic glutathione (GSH), its efficacy against AKI remains limited, suggesting distinct mechanisms of renal injury. We investigated the role of GSH homeostasis and potential beneficial effects of NAC and Fomepizole (4-methylpyrazole) in APAP-induced liver and kidney injury using female C57BL/6J mice, which naturally lack renal CYP2E1 expression and therefore provide a unique model to examine nephrotoxicity independent of renal CYP2E1-mediated bioactivation. Female mice received APAP (300 or 600 mg/kg) with or without buthionine sulfoximine (BSO, 50 mg/kg) to inhibit GSH synthesis, NAC (500 mg/kg) to promote GSH recovery, or Fomepizole (50 mg/kg) to inhibit CYP2E1-mediated bioactivation. APAP overdose caused severe hepatotoxicity, whereas kidney injury remained minimal during the first 24 h. Although BSO markedly enhanced hepatic GSH depletion and liver injury, it did not significantly worsen renal dysfunction or tubular injury. In contrast, NAC substantially reduced liver injury and improved survival after severe APAP overdose; yet renal dysfunction progressed by 48 h, accompanied by tubular vacuolation, increased KIM-1 and osteopontin expression, and tubular cell death. Fomepizole substantially protected both organs from injury. These findings demonstrate that delayed APAP-induced AKI can develop independent of the severity of liver injury, even with effective NAC-mediated hepatoprotection. On the other hand, Fomepizole protects against AKI in female mice by a CYP2E1-independent mechanism.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 23 Oct 2026.
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