Nimesulide-induced electrophile stress activates Nrf2 in human hepatocytes and mice but is not sufficient to induce hepatotoxicity in Nrf2-deficient mice.

Nimesulide is a widely prescribed nitroaromatic sulfoanilide-type nonsteroidal anti-inflammatory drug that, despite its favorable safety profile, has been associated with rare cases of idiosyncratic drug-induced liver injury (DILI). Because reactive metabolites have been implicated in DILI, we aimed at investigating whether hepatic bioactivation of nimesulide produces a protein-reactive intermediate in hepatocytes. Also, we explored whether nimesulide can activate the transcription factor Nrf2 that would protect from drug-induced hepatocyte injury. We found that [14C]-nimesulide covalently bound to human liver microsomes (<50 pmol/mg under standard conditions) or immortalized human hepatocytes in a sulfaphenazole-sensitive, rifampicin-inducible manner; yet the overall extent of binding was modest. Although exposure of hepatocytes to nimesulide was not associated with increased net levels of superoxide anion, nimesulide (100 μM, 24 h) caused nuclear translocation of Nrf2 in a sulfaphenazole-sensitive manne...