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Signal Transduction Pathways Involved in Drug-Induced Liver Injury

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Adverse Drug Reactions

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 196))

Abstract

Hepatocyte death following drug intake is the critical event in the clinical manifestation of drug-induced liver injury (DILI). Traditionally, hepatocyte death caused by drugs had been attributed to overwhelming oxidative stress and mitochondria dysfunction caused by reactive metabolites formed during drug metabolism. However, recent studies have also shown that signal transduction pathways activated/inhibited during oxidative stress play a key role in DILI. In acetaminophen (APAP)-induced liver injury, hepatocyte death requires the sustained activation of c-Jun kinase (JNK), a kinase important in mediating apoptotic and necrotic death. Inhibition of JNK using chemical inhibitors or knocking down JNK can prevent hepatocyte death even in the presence of extensive glutathione (GSH) depletion, covalent binding, and oxidative stress. Once activated, JNK translocates to mitochondria, to induce mitochondria permeability transition and trigger hepatocyte death. Mitochondria are central targets where prodeath kinases such as JNK, prosurvival death proteins such as bcl-xl, and oxidative damage converge to determine hepatocyte survival. The importance of mitochondria in DILI is also observed in the Mn-SOD heterozygous (+/−) model, where mice with less mitochondrial Mn-SOD are sensitized to liver injury caused by certain drugs. An extensive body of research is accumulating suggesting a central role of mitochondria in DILI. Drugs can also cause redox changes that inhibit important prosurvival pathways such as NF-κB. The inhibition of NF-κB by subtoxic doses of APAP sensitizes hepatocyte to the cytotoxic actions of tumor necrosis factor (TNF). Many drugs will induce liver injury if simultaneously treated with LPS, which promotes inflammation and cytokine release. Drugs may be sensitizing hepatocytes to the cytotoxic effects of cytokines such as TNF, or vice versa. Overall many signaling pathways are important in regulating DILI, and represent potential therapeutic targets to reduce liver injury caused by drugs.

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Abbreviations

APAP:

Acetaminophen

AMAP:

N-acetyl-m-aminophenol

ASK-1:

Apoptosis signaling-regulating kinase 1

CYP:

Cytochrome P450

DILI:

Drug-induced liver injury

DNASE1:

Deoxyribonuclease 1

GSH:

Glutathione

GSK-3β:

Glycogen synthase kinase-3β

JNK:

cJun N-terminal protein kinase

LPS:

Lipopolysaccharide

MPT:

Mitochondria permeability transition

NAC:

N-acetylcysteine

NAPQI:

N-acetyl-p-benzo-quinoneimine

NO:

Nitric oxide

Nrf-2:

NF E2-related factor 2

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

TNF:

Tumor necrosis factor

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  1. Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, 2011 Zonal Ave, HMR 101, Los Angeles, CA, 90089-9121, USA

    Derick Han

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  1. Derick Han
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  2. Mie Shinohara
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  3. Maria D. Ybanez
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  4. Behnam Saberi
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  5. Neil Kaplowitz
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Correspondence to Derick Han .

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    Jack Uetrecht (Professor of Pharmacy and Medicine, Canada Research Chair in Adverse Drug Reactions) (Professor of Pharmacy and Medicine, Canada Research Chair in Adverse Drug Reactions)

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Han, D., Shinohara, M., Ybanez, M.D., Saberi, B., Kaplowitz, N. (2010). Signal Transduction Pathways Involved in Drug-Induced Liver Injury. In: Uetrecht, J. (eds) Adverse Drug Reactions. Handbook of Experimental Pharmacology, vol 196. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00663-0_10

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