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

Abstract

Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local O(2) supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca(2+)-dependent ATPase, reduced capability to sequester Ca(2+) within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.

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.