• Dotan Uzi, Liran Barda, Viviana Scaiewicz, Maya Mills, Tobias Mueller, Agueda Gonzalez-Rodriguez, Angela M Valverde, Takao Iwawaki, Yaacov Nahmias, Ramnik Xavier, Ray T Chung, Boaz Tirosh, and Oren Shibolet.
• Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University, Jerusalem, Israel.
• J. Hepatol. 2013 Sep 1; 59 (3): 495-503.

Background & AimsThe 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.MethodsA toxic dose of APAP was orally administered to wild type (wt) and CHOP knockout (KO) mice and damage mechanisms were assessed.ResultsCHOP KO mice were protected from APAP induced damage and exhibited decreased liver necrosis and increased survival. APAP metabolism in CHOP KO mice was undisturbed and glutathione was depleted at similar kinetics to wt. ER stress and UPR activation were overtly seen 12h following APAP administration, a time that coincided with strong upregulation of CHOP. Remarkably, CHOP KO but not wt mice exhibited hepatocyte proliferation at sites of necrosis. In vitro, large T immortalized CHOP KO hepatocytes were protected from APAP toxicity in comparison to wt control cells.ConclusionsCHOP 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.Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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