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Cell Death in Drug-Induced Liver Injury

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Cellular Injury in Liver Diseases

Part of the book series: Cell Death in Biology and Diseases ((CELLDEATH))

Abstract

Drug-induced liver injury (DILI) represents a spectrum of clinical presentations such as acute hepatocellular liver injury resulting in liver failure, cholestasis and jaundice, nodular regenerative hyperplasia, sinusoidal obstruction syndrome, or subclinical injury which is detected during routine testing. Furthermore, DILI can be divided into acute and chronic hepatotoxicity and also into direct dose-dependent toxicity versus idiosyncratic DILI. In all of these instances, the ultimate outcome of liver injury is often cell death. The cell death subroutine, however, depends largely on whether a toxic metabolite leads to the activation of the adaptive immune system resulting in hepatocyte killing via death receptor (DR) engagement, or if it is intrinsically toxic to hepatocytes. DR-mediated cell death is usually apoptotic while intrinsic toxicity can activate apoptosis or necrosis pathways. Autophagy is an alternative form of cell death which has been implicated in some drug toxicity models. However, for the most part activation of autophagy (and mitophagy in particular) seems to have a protective effect by removal of damaged organelles that would otherwise produce oxidative or proteolytic stress. In this chapter, we will explore the cell death subroutines, apoptosis, necrosis, necroptosis, and autophagy, as they pertain to drug-induced hepatotoxicity.

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Abbreviations

ALF :

Acute liver failure

APAP :

Acetaminophen

APAF1 :

Apoptotic peptidase-activating factor-1

ASK1 :

Apoptosis signal-regulating kinase 1

ASMase :

Acid sphingomyelinase

ATF6 :

Activating transcription factor 6

ATG :

Autophagy-related genes

Cbl-b1 :

Casitas B lineage lymphoma-B1

CCL4 :

Carbon tetrachloride

CHOP :

CCAAT-enhancer-binding protein homologous protein

cIAP :

Cellular inhibitor of apoptosis 1 and 2

Cr :

Chromium

CTLA4 :

Cytotoxic T-lymphocyte-associated protein 4

DILI :

Drug-induced liver injury

DR :

Death receptor

ER Stress :

Endoplasmic reticulum stress

ETC :

Electron transport chain

FADD :

Fas-associated protein with death domain

GRP78 :

Glucose regulatory peptide 78

GSH :

Glutathione

GSK3b :

Glycogen synthase kinase 3 beta

GWAS :

Genome-wide association study

INH :

Isonizaide

JNK :

c-Jun N terminal kinase

K18 :

Keratin 18

KCC :

King’s college criteria

KO :

Knockout

HLA :

Human leukocyte antigen

HMGB1 :

High-mobility group box 1

IRE1α:

Inositol-requiring enzyme 1α

IDILI :

Idiosyncratic drug-induced liver injury

LPS :

Lipopolysaccharides

LSEC :

Liver sinusoidal endothelial cells

MAPK :

Mitogen-activated protein kinase

MDSC :

Myeloid-derived suppressor cells

MEF :

Mouse embryonic fibroblasts

MELD :

Model for end-stage liver disease

MHC :

Major histocompatibility complex

miR :

Micro RNA

MDB :

Mallory-Denk bodies

MKK4 :

Mitogen-activated protein kinase kinase 4

MLKL :

Mixed lineage kinase domain-like

MOMP :

Mitochondrial outer membrane permeabilization

MPT :

Mitochondrial permeability transition pore

mTOR :

Mammalian target of rapamycin

NAFLD :

Non-alcoholic fatty liver disease

NASH :

Non-alcoholic steatohepatitis

NFκB :

Nuclear factor κB

NK :

Natural killer

PD-1 :

Programmed cell death protein-1

PERK :

Protein kinase RNA-like ER kinase

PKC :

Protein kinase C

POLG :

Polymerase γ

PTPN6 :

Phospho-tyrosine phosphatase, non-receptor type 6

RIPK1 :

Receptor interacting protein kinase 1

RIPK3 :

Receptor interacting protein kinase 3

ROS :

Reactive oxygen species

Sab :

SH3BP5, SH3 domain-binding protein that preferentially associates with Bruton’s tyrosine kinase

SMAC :

Second mitochondria-derived activator of caspases

TAB2/3 :

TAK1-binding protein 2/3

TAK1 :

Transforming growth factor-β-activated kinase 1

TRAF2 :

TNF receptor-associated factor 2

TRAIL :

TNF-related apoptosis-inducing ligand

TNF :

Tumor necrosis factor

TNFR :

Tumor necrosis factor receptor

TRADD :

TNFR1-associated via death domain

UPR :

Unfolded protein response

VPA :

Valproic acid

WT :

Wild type

XIAP :

X-chromosome-linked inhibitor of apoptosis protein

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Acknowledgment

This work was supported by NIH grants K08DK109141(LD), R01DK067215 (NK), P30DK048522 (NK).

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  1. Division of GI/Liver, Department of Medicine, Research Center for Liver Disease, Keck School of Medicine, University of Southern California, 2011 Zonal Ave, HMR 101, Los Angeles, CA, 90033, USA

    Lily Dara & Neil Kaplowitz

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  1. Lily Dara
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  2. Neil Kaplowitz
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Correspondence to Neil Kaplowitz .

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Editors and Affiliations

  1. Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, USA

    Wen-Xing Ding

  2. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Xiao-Ming Yin

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Dara, L., Kaplowitz, N. (2017). Cell Death in Drug-Induced Liver Injury. In: Ding, WX., Yin, XM. (eds) Cellular Injury in Liver Diseases. Cell Death in Biology and Diseases. Springer, Cham. https://doi.org/10.1007/978-3-319-53774-0_1

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