Signal Transduction Pathways Involved in Drug-Induced Liver Injury

  • Derick HanEmail author
  • Mie Shinohara
  • Maria D. Ybanez
  • Behnam Saberi
  • Neil Kaplowitz
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 196)


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.


Acetaminophen Oxidative stress Redox JNK Mitochondria 







Apoptosis signaling-regulating kinase 1


Cytochrome P450


Drug-induced liver injury


Deoxyribonuclease 1




Glycogen synthase kinase-3β


cJun N-terminal protein kinase




Mitochondria permeability transition






Nitric oxide


NF E2-related factor 2


Reactive nitrogen species


Reactive oxygen species


Tumor necrosis factor


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Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • Derick Han
    • 1
    Email author
  • Mie Shinohara
  • Maria D. Ybanez
  • Behnam Saberi
  • Neil Kaplowitz
  1. 1.Research Center for Liver DiseasesKeck School of Medicine, University of Southern CaliforniaLos AngelesUSA

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