title: Xenobiotics and autoimmunity: does acetaminophen cause primary biliary cirrhosis?
abstract: The serologic hallmark of primary biliary cirrhosis (PBC) is the presence of antimitochondrial autoantibodies (AMAs) directed against the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). The PBC-related autoepitope of PDC-E2 contains lipoic acid, and previous work has demonstrated that mimics of lipoic acid following immunization of mice lead to a PBC-like disease. Furthermore, approximately one-third of patients who have ingested excessive amounts of acetaminophen (paracetamol) develop AMA of the same specificity as patients with PBC. Quantitative structure-activity relationship (QSAR) data indicates that acetaminophen metabolites are particularly immunoreactive with AMA, and we submit that in genetically susceptible hosts, electrophilic modification of lipoic acid in PDC-E2 by acetaminophen or similar drugs can facilitate a loss of tolerance and lead to the development of PBC.
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA. psleung@ucdavis.edu
authors.forename: Patrick S C
authors.initials: PS
authors.lastname: Leung
authors.forename: Kit
authors.initials: K
authors.lastname: Lam
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kurth
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000139:chemically induced* / Q000276:immunology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D008063:Thioctic Acid / Q000378:metabolism; D015262:Xenobiotics / Q000276:immunology* / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D011768:Pyruvate Dehydrogenase Complex; D015262:Xenobiotics; D000082:Acetaminophen; D008063:Thioctic Acid