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Xenobiotics and autoimmunity: does acetaminophen cause primary biliary cirrhosis?

Authors
  • Ps, Leung
  • Kit S. Lam
  • Mj, Kurth
  • Rl, Coppel
  • Me, Gershwin
Type
Published Article
Journal
Trends in Molecular Medicine
Publisher
Elsevier
Volume
18
Issue
10
Pages
577–582
Identifiers
DOI: 10.1016/j.molmed.2012.07.005
Source
Kit Lam Lab
License
Unknown

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.

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