title: Biochemical and cellular mechanisms of toxic liver injury.
abstract: The pathogenesis of drug- or toxin-induced liver injury usually involves the participation of toxic metabolites that either elicit an immune response or directly affect the biochemistry of the cell. The clinical appearance of hepatitis is then a consequence of cell death mediated by either the extrinsic immune system (e.g., cytotoxic T cells) or intracellular stress. Intracellular stress can lead to apoptotic or necrotic cell death, depending on the extent of mitochondrial involvement and the balance of factors that activate and inhibit the Bcl 2 family of proteins and the caspases. Drug metabolites can undergo or promote a variety of chemical reactions, including covalent binding, depletion of reduced glutathione, or oxidative stress with consequent effects on proteins, lipids, and DNA. These chemical consequences can directly affect organelles such as mitochondria, cytoskeleton, endoplasmic reticulum, microtubules, or nucleus or indirectly influence these organelles through activation or inhibition of signaling kinases, transcription factors, and gene expression profiles. The outcome may be either triggering of the necrotic or apoptotic process or sensitization to the lethal action of cytokines of the immune system intrinsic to the liver.
authors.affiliation: USC School of Medicine, Los Angeles, California 90033, USA. kaplowit@hsc.usc.edu
authors.forename: Neil
authors.initials: N
authors.lastname: Kaplowitz
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000503:physiopathology*; D016207:Cytokines / Q000494:pharmacology; D064420:Drug-Related Side Effects and Adverse Reactions; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000473:pathology*; D008928:Mitochondria / Q000502:physiology; D009336:Necrosis; D018384:Oxidative Stress; D015398:Signal Transduction; D014118:Toxins, Biological / Q000009:adverse effects
chemical_list: D016207:Cytokines; D014118:Toxins, Biological; D020169:Caspases