外源性化合物与自身免疫：对乙酰氨基酚会导致原发性胆汁性肝硬化吗？
Xenobiotics and autoimmunity: does acetaminophen cause primary biliary cirrhosis?
机构信息
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA.
出版信息
Trends Mol Med. 2012 Oct;18(10):577-82. doi: 10.1016/j.molmed.2012.07.005. Epub 2012 Aug 21.
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.
摘要
原发性胆汁性肝硬化（PBC）的血清学标志是存在针对丙酮酸脱氢酶复合物（PDC-E2）E2 亚单位的抗线粒体自身抗体（AMAs）。PDC-E2 的 PBC 相关自身抗原含有硫辛酸，以前的工作表明，在给小鼠免疫模拟硫辛酸后，会导致类似于 PBC 的疾病。此外，大约三分之一摄入过量对乙酰氨基酚（扑热息痛）的患者会产生与 PBC 患者相同特异性的 AMA。定量构效关系（QSAR）数据表明，对乙酰氨基酚代谢物与 AMA 的免疫反应特别强，我们认为，在遗传易感宿主中，对乙酰氨基酚或类似药物对 PDC-E2 中硫辛酸的亲电修饰可以促进耐受性丧失，并导致 PBC 的发展。
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