Figure 1.

Mechanisms of four main types of DILI. (A) Autoimmune-like DILI. Reactive metabolites generated by CYPs and other drug-metabolizing enzymes can covalently bind liver proteins and form drug-modified self-antigens recognized by immune cells. Release of damage associated molecular patterns (DAMPs) resulting from hepatocyte stress induced by parental drug or their reactive metabolites can also contribute to the activation of immune cells. (B) Steatosis. Drugs may alter fatty acid (FFA) homeostasis in the liver by several mechanisms, including the reduction in FFA export as very low-density lipoproteins (VLDL), impairment of FFA entry in the mitochondria, direct inhibition of mitochondrial β-oxidation enzymes, disruption of mitochondrial respiratory chain (MRC) or depletion of mitochondrial DNA (mtDNA). Non-metabolized FFA are esterified to form triglycerides and accumulate in the cytoplasm of hepatocytes as lipid droplets. Drug-induced mitochondrial dysfunction can result in ATP depletion and increased formation of reactive oxygen species (ROS) and subsequent hepatocyte injury. Further activation of Kupffer and stellate cells by DAMPs and/or cytokines released by damaged hepatocytes may induce inflammatory and fibrotic responses in the liver and contribute to steatosis progression to steatohepatitis or fibrosis. (C) Phospholipidosis. Drugs can accumulate in lysosomes and decrease phospholipids (PLP) degradation by direct inhibition of phospholipases or by formation of degradation-resistant drug–PLP complexes. Drug-induced alterations of lysosomal function, with loss of hydrolytic enzymes due to release of enzymes or alterations in enzyme synthesis or transport, as well as changes in expression of genes involved in PLP metabolism, may result in PLP accumulation and formation of lamellar bodies. (D) Cholestasis. Drugs may disrupt homeostasis of bile acid in the liver by direct inhibition of hepatobiliary transporters located at the sinusoidal and canalicular membranes of hepatocytes or by alteration of key processes involved in the expression and/or localisation of transport proteins. Accumulation of bile acids up to cytotoxic concentrations can result in damage to parenchymal liver cells and bile ducts.