Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

Figure 1 Schematic representation of subtoxic damage of hepatocyte in response to moderate dose of drug. Drug molecule activates Kupffer cells is metabolically processed by hepatocytes. These events may result in hepatocyte stress which is worsened by the intervention of reactive oxygen species (ROS) and nitrogen species from activated endothelial cells. Final result is apoptotic death and Ito cells activation with promotion of fibrosis. EC-GF: Endothelial cell growth factor; IL1: Interleukin 1; IL1β: Interleukin 1β; RNI: Reactive nitrogen intermediates; ROS: Reactive oxygen species; TGF-β: Transforming growth factor β; TNF: Tumor necrosis factor α.

Figure 2 Schematic representation of toxic damage of hepatocyte in response to high dose of drug. High drug amount is processed by hepatocytes with production of reactive metabolites which induce cell injury. Toxic products and chemotactic factors released by damaged hepatocytes stimulate the activation of Kupffer and endothelial cells with a subsequent delivery of reactive oxygen (ROS) and nitrogen species. The intracellular damages result in necrotic death. LPO: Lipid peroxidation; LTB4: Leukotriene B4.

Figure 3 Schematic representation of mitochondrial oxido-reductase system. Several drug molecules directly or after metabolic release of toxic intermediates can cause mitochondrial alterations at different levels. The following impairment of the energetic and redox balance finally triggers apoptotic or necrotic processes according to a poor or sufficient ATP level. Important regulatory mechanisms rely on the glutathione dependent redox status of proteins. GSH: Reduced glutathione; GSSG: Oxidized glutathione; GSH-Px: Glutathione peroxidase; GSSG-RX: Glutathione reductase; iNOS: Inducible nitric oxide synthetase; NO: Nitric oxide; PSH: Protein sulphydrils; PS-SG: Protein mixed disulfides; PS-SP: Protein-protein disulfides; TRx: Thioredoxin; TRx-R: Thioredoxin reductase; TR-S₂: Oxidized thioredoxin.