Journal of hepatology
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Journal of hepatology · Sep 2013
CHOP is a critical regulator of acetaminophen-induced hepatotoxicity.
The liver is a major site of drug metabolism and elimination and as such is susceptible to drug toxicity. Drug induced liver injury is a leading cause of acute liver injury, of which acetaminophen (APAP) is the most frequent causative agent. APAP toxicity is initiated by its toxic metabolite NAPQI. However, downstream mechanisms underlying APAP induced cell death are still unclear. Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have recently emerged as major regulators of metabolic homeostasis. UPR regulation of the transcription repressor CHOP promotes cell death. We analyzed the role of UPR and CHOP in mediating APAP hepatotoxicity. ⋯ CHOP upregulation during APAP induced liver injury compromises hepatocyte survival in various mechanisms, in part by curtailing the regeneration phase following liver damage. Thus, CHOP plays a pro-damage role in response to APAP intoxication.