Xenobiotics and autoimmunity: does acetaminophen cause primary biliary cirrhosis?

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 mim...

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Bibliographic Details
Published in:Trends in molecular medicine 2012-10, Vol.18 (10), p.577-582
Main Authors: Leung, Patrick S.C, Lam, Kit, Kurth, Mark J, Coppel, Ross L, Gershwin, M. Eric
Format: Article
Language:English
Subjects:
Acetaminophen - administration & dosage
Acetaminophen - adverse effects
Acetaminophen - immunology
Animals
Autoantibodies - immunology
Autoimmunity
Humans
Liver Cirrhosis, Biliary - chemically induced
Liver Cirrhosis, Biliary - immunology
Mice
Mitochondria - drug effects
Mitochondria - metabolism
Pathology
Pyruvate Dehydrogenase Complex - metabolism
Quantitative Structure-Activity Relationship
Thioctic Acid - metabolism
Xenobiotics - immunology
Xenobiotics - metabolism
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Summary: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.
ISSN:1471-4914
1471-499X
DOI:10.1016/j.molmed.2012.07.005