Drug-induced liver disease.

The various forms and manifestations of drug-induced liver disease depend on the operation and interaction of several potential factors. First, there is metabolism by the hepatic microsomal mixed-function oxidase (MFO) enzyme system, the most important component of which is cytochrome P-450. The microsomal membranes and the MFO enzymes are capable of induction (increase in structure and function). Second, for drug-induced liver damage to ensue, the drug must have certain structural properties so that upon metabolic conversion, activated (toxic) metabolites are produced. Third, in certain instances the normal tissue glutathione level is critical for normal excretion of a water-soluble metabolite; otherwise, with depletion of tissue macromolecules (mostly proteins) occurs, resulting in irreversible tissue necrosis. Lastly, although still a point of some controversy, in some instances genetically determined, metabolic, predisposing factors that favor the toxicity pathway may be present in a given patient, such as a patient who is a rapid acetylator. There may be other genetically determined abnormalities in drug metabolism that produce either abnormal metabolites or immunochemically reactive substances from a given agent, but these have not yet been identified.