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
