title: The chemical, genetic and immunological basis of idiosyncratic drug-induced liver injury.
abstract: Idiosyncratic drug reactions can be extremely severe and are not accounted for by the regular pharmacology of a drug. Thus, the mechanism of idiosyncratic drug-induced liver injury (iDILI), a phenomenon that occurs with many drugs including β-lactams, anti-tuberculosis drugs and non-steroidal anti-inflammatories, has been difficult to determine and remains a pressing issue for patients and drug companies. Evidence has shown that iDILI is multifactorial and multifaceted, which suggests that multiple cellular mechanisms may be involved. However, a common initiating event has been proposed to be the formation of reactive drug metabolites and covalently bound adducts. Although the fate of these metabolites are unclear, recent evidence has shown a possible link between iDILI and the adaptive immune system. This review highlights the role of reactive metabolites, the recent genetic innovations which have provided molecular targets for iDILI, and the current literature which suggests an immunological basis for iDILI.
authors.affiliation: Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, England.
authors.forename: A
authors.initials: A
authors.lastname: Tailor
authors.affiliation: Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, England.
authors.forename: L
authors.initials: L
authors.lastname: Faulkner
authors.affiliation: Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, England.
authors.forename: D J
authors.initials: DJ
authors.lastname: Naisbitt
authors.affiliation: Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, England bkpark@liv.ac.uk.
authors.forename: B K
authors.initials: BK
authors.lastname: Park
mesh_terms: D019980:Amoxicillin-Potassium Clavulanate Combination / Q000009:adverse effects; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D005436:Floxacillin / Q000009:adverse effects; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects; D004364:Pharmaceutical Preparations / Q000378:metabolism
chemical_list: D004364:Pharmaceutical Preparations; D005436:Floxacillin; D019980:Amoxicillin-Potassium Clavulanate Combination; D007538:Isoniazid
keywords: DILI; Idiosyncratic drug–induced liver injury; adduct; pharmacogenomics