Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria

Abstract

Drugs that cause liver injury often “stress” mitochondria and activate signal transduction pathways important in determining cell survival or death. In most cases, hepatocytes adapt to the drug-induced stress by activating adaptive signaling pathways, such as mitochondrial adaptive responses and erythroid 2-related factor 2 (Nrf-2), a transcription factor that upregulates antioxidant defenses. Due to adaptation, drugs alone rarely cause liver injury, with acetaminophen being the notable exception. Drug-induced liver injury (DILI) usually involves other extrinsic factors, such as the adaptive immune system, that cause “stressed” hepatocytes to become injured; leading to idiosyncratic DILI, the rare and unpredictable adverse drug reaction in the liver. Hepatocyte injury, due to drug and extrinsic insult, causes a second wave of signaling changes associated with adaptation, cell death, and repair. If the stress and injury reach a critical threshold, then death signaling pathways such as JNK become dominant and hepatocytes enter a failsafe mode to undergo self-destruction. DILI can be seen as an active process involving recruitment of death signaling pathways that mediate cell death rather than a passive process due to overwhelming biochemical injury. In this review, we highlight the role of signal transduction pathways, which frequently involve mitochondria, in the development of DILI.

Evaluation of Three-Dimensional Cultured HepG2 Cells in a Nano Culture Plate System: an In Vitro Human Model of Acetaminophen Hepatotoxicity

“…The reason for the inhibiting mechanisms of JNK phosphorylation by CyA may be discontinuation of the feedback loop between JNK pathway activation and mitochondrial damage. In fact, phosphorylation of JNK and subsequent mitochondrial damage is not one-way; mitochondrial damage may induce further JNK phosphorylation (2nd hit), and it may amplify the decrease in mitochondrial membrane potential or mitochondrial damage in APAP-induced hepatotoxicity (34,44) (Supplementary Fig. 2).…”

Real-time monitoring of oxygen uptake in hepatic bioreactor shows CYP450-independent mitochondrial toxicity of acetaminophen and amiodarone

“…Oxygen uptake is a critical measurement of mitochondrial function and metabolic activity (Green and Reed 1998;Han et al 2013). To reliably measure oxygen on the microscale, we used a ruthenium-based dye whose phosphorescence is quenched in the presence of oxygen.…”

“…One of the main intracellular targets of drug-induced liver injury is mitochondrial function (Han et al 2013), either through direct damage to the respiratory complex (e.g., NAPQI) or though secondary mechanisms such as ER stress (e.g., tunicamycin) (Han et al 2013;Yuan and Kaplowitz 2013). Currently, end-point assays such as MTT or JC1 staining are used to evaluate mitochondrial function or its membrane potential, respectively.…”

Noncoding RNAs as therapeutics for acetaminophen-induced liver injury

“…However, when sulfation is saturated (8), additional quantities of APAP are metabolized by Cyp2E1 and NAPQI accumulation initiates liver toxicity. Excess NAPQI causes significant depletion of glutathione, protein adduct formation especially in mitochondria (9,10) and a mitochondrial oxidative and nitrosative stress (11), which is then amplified by translocation of c-Jun N-terminal kinase (JNK) to the mitochondria (12,13). This triggers the opening of the mitochondrial permeability transition pore resulting in collapse of the membrane potential, cessation of ATP formation, and matrix swelling (14).…”