immune-mediated drug-induced hepatic diseases
Unstable metabolites derived from the metabolism of the drug may bind to cellular proteins or macromolecules, leading to a direct toxic effect on hepatocytes.
Protein adducts formed in the metabolism of the drug may be recognized by the immune system as neoantigens.
Immunocyte activation may then generate autoantibodies and cell-mediated immune responses, which in turn damage the hepatocytes.
Cytochromes 450 are the major oxidative catalysts in drug metabolism, and they can form a neoantigen by covalently binding with the drug metabolite that they produce. Autoantibodies that develop are selectively directed against the particular cytochrome isoenzyme that metabolized the parent drug.
The hapten hypothesis proposes that the drug metabolite can act as a hapten and can modify the self of the individual by covalently binding to proteins.
The danger hypothesis proposes that the immune system only responds to a foreign antigen if the antigen is associated with a danger signal, such as cell stress or cell death.
Most clinically overt adverse hepatic events associated with drugs are unpredictable, and they have intermediate (1 to 8 weeks) or long latency (up to 12 months) periods characteristic of hypersensitivity reactions.
Immune-mediated drug-induced liver disease nearly always disappears or becomes quiescent when the drug is removed.
Exemples
methyldopa
minocycline
nitrofurantoin
References
Liu ZX, Kaplowitz N. Immune-mediated drug-induced liver disease. Clin Liver Dis. 2002 Aug;6(3):755-74. PMID: #12362579#