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Int. J. Mol. Sci. 2017, 18(5), 1018; doi:10.3390/ijms18051018

Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis

1,2,†
,
1,2,†
and
1,2,*
1
Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
2
Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editors: Rolf Teschke and Gaby Danan
Received: 6 April 2017 / Revised: 5 May 2017 / Accepted: 7 May 2017 / Published: 9 May 2017
(This article belongs to the Special Issue Molecular Research on Drug Induced Liver Injury)
View Full-Text   |   Download PDF [1116 KB, uploaded 9 May 2017]   |  

Abstract

Drug-induced liver injury (DILI) can broadly be divided into predictable and dose dependent such as acetaminophen (APAP) and unpredictable or idiosyncratic DILI (IDILI). Liver injury from drug hepatotoxicity (whether idiosyncratic or predictable) results in hepatocyte cell death and inflammation. The cascade of events leading to DILI and the cell death subroutine (apoptosis or necrosis) of the cell depend largely on the culprit drug. Direct toxins to hepatocytes likely induce oxidative organelle stress (such as endoplasmic reticulum (ER) and mitochondrial stress) leading to necrosis or apoptosis, while cell death in idiosyncratic DILI (IDILI) is usually the result of engagement of the innate and adaptive immune system (likely apoptotic), involving death receptors (DR). Here, we review the hepatocyte cell death pathways both in direct hepatotoxicity such as in APAP DILI as well as in IDILI. We examine the known signaling pathways in APAP toxicity, a model of necrotic liver cell death. We also explore what is known about the genetic basis of IDILI and the molecular pathways leading to immune activation and how these events can trigger hepatotoxicity and cell death. View Full-Text
Keywords: hepatotoxicity; human leukocyte antigen (HLA); adaptation; acetaminophen; DILI; apoptosis; necrosis hepatotoxicity; human leukocyte antigen (HLA); adaptation; acetaminophen; DILI; apoptosis; necrosis
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MDPI and ACS Style

Iorga, A.; Dara, L.; Kaplowitz, N. Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis. Int. J. Mol. Sci. 2017, 18, 1018.

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