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 Bcl₂ 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.

KEYWORDS

Hepatotoxicity - apoptosis - necrosis - mitochondria - caspases - oxidative stress - cytokines - intracellular signaling - gene expression

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