Dissecting the molecular pathophysiology of drug-induced liver injury

Figure 1 Pathophysiology of drug-induced liver injury. Schematic representation of paracetamol toxicology. Metabolism of acetaminophen (APAP) or carbon tetrachloride (CCl₄) catalyzed by CYP2E1 enzyme causes the generation of an intermediate reactive compound which causes covalent bonds, glutathione (GSH) depletion and increased in oxidative stress. Thioredoxin-1 (Trx-1) normally binds the N-terminal domain of Apoptosis signal-regulating kinase 1 (ASK1) and inhibits kinase activity. Reactive oxygen species (ROS) accumulation oxidizes and consequently removes Trx-1 from Trx-ASK1 complexes, leading to activation of ASK1 and subsequent apoptosis signalling cascade. Then c-Jun N-terminal kinases (JNK) translocates into the mitochondria and alters of the mitochondrial membrane potential, which triggers cell death. DILI: Drug-induced liver injury. MPT: Membrane permeability transition; LPO: Lipid peroxidation; NAPQI: N-acetyl-p-benzoquinone imine.