Mechanisms of drug-induced liver injury

Abstract

Drug-induced liver injury (DILI) represents a broad spectrum of liver manifestations. However, the most common manifestation is hepatocyte death following drug intake. DILI can be predictable and dose dependent with a notable example of acetaminophen toxicity. Idiosyncratic DILI occurs in an unpredictable fashion at low frequencies, implying that environmental and genetic factors alter the susceptibility of individuals to the insult (drugs).

Keywords: Adaptive immunity; Cell death; HLA associations; Idiosyncratic drug-induced liver injury; Mitochondria; Oxidative stress; Reactive metabolites; Stress signaling.

Fig. 1

c-Jun N-terminal kinase (JNK) signaling and mitochondrial involvement in the death of hepatocytes. Sustained JNK activation and mitochondrial reactive oxygen species (ROS) generation are critical to induce cell death, particularly in the APAP model. In the APAP model, profound glutathione (GSH) depletion and covalent binding of NAPQI, lead to generation of mitochondrial ROS which activates mitogen activated protein kinases (MAPK) including apoptosis signal-regulating kinase-1 (ASK1) and mixed-lineage kinase-3 (MLK3). Both ASK1 and MLK3 activate MKK4/7 which in turn phosphorylates and activates JNK. Phosphorylated JNK translocates to mitochondria where it binds to and phosphorylates Sab, a mitochondrial outer membrane scaffold protein. This somehow leads to further impairment of electron transport chain (ETC) and enhancement of mitochondrial ROS generation. This self-amplifying process leads to sustained JNK activation and overwhelming production of mitochondrial ROS in the APAP model. As a result, mitochondrial permeability transition (MPT) collapses ATP production and necrosis occurs. In the model of tumor necrosis factor-a (TNF-a)-TNF/D-galactosamine, sustained JNK activation leads to mitochondrial outer membrane permeabilization (MOMP) and apoptosis by modulating the Bcl2 family.

Fig. 2

Hypothetical mechanisms of idiosyncratic drug-induced liver injury (IDILI). Adaptive immune response plays a major role in IDILI. This may be to some extent regulated by cellular events induced by drug and reactive metabolites. Specifically, drug or reactive metabolites may generate hazards in hepatocytes by inducing endoplasmic reticulum (ER) stress, generating ROS, activating stress signaling, impairing mitochondrial function, etc. To defend against these hazards, hepatocytes respond through adaptive mechanisms including nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling, mitophagy and autophagy to cope with stress. The innate and adaptive immune systems can adapt to dampen the response. The ultimate outcome of liver is no injury, mild injury or severe injury. Although non-immune IDILI remains a theoretical possibility as a consequence of the hazards of reactive metabolites, aside from a small number of drugs which directly damage mitochondria, there are very few, if any, proven examples of this possibility.