Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis
Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis
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DOI：
10.1016/j.jaut.2006.06.002
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发表时间：
2006-08-01
影响因子：
12.8
通讯作者：
Gershwin, M. Eric
中科院分区：
文献类型：
--
作者：
Rieger, Roman;Leung, Patrick S. C.;Gershwin, M. Eric
抗线粒体抗体（AMA）在自身免疫性血清学反应物中是独一无二的，因为它们与原发性胆汁性肝硬化（PBC）指数有极高的相关性。这种自身抗体反应仅针对线粒体2-氧酸脱氢酶复合物的脂酰基结构域，这促使我们以外源性药物的形式寻找环境半模体，并导致我们鉴定出2-辛酸是AMA的高亲和力反应物。为了关注AMA与外源性修饰的自肽结合所需的化学特征，我们使用一组炔酸化合物进行了定量构效关系（QSAR）研究，包括检查碳链的长度和鉴定的模位中的三键的位置。对三键位置不同的辛酰胺的分析表明，只有2-辛酰胺与PBC血清反应强烈。此外，在不同碳链长度的2-烷基酰胺中，2-辛烷-、2-壬烷-（特别是）和2-癸酰胺表现出最高的反应活性。因此，ama阳性PBC血清识别的外源修饰表位的最佳化学结构由2-nonynoic酸提供。该化合物的甲酯在职业性接触的12,945种化合物中排名第2324位，由于其在化妆品中的使用，女性患病率为80%。我们的研究结果说明了抗pdc - e2的不寻常的多反应性，并支持了这种自身抗体和PBC本身发生的表位模仿的观点。(c) 2006 Elsevier Ltd.版权所有。
Anti mitochondrial antibodies (AMA) are unique among autoimmune serologic reactants because of their extremely high association with the index disease primary biliary cirrhosis (PBC). This autoantibody response is specifically directed only to the lipoyl domain of the mitochondrial 2-oxo-acid dehydrogenase complexes, which prompted us to search for environmental mimotopes in the form of xenobiotics and led to our identification of 2-octynoic acid as a high-affinity reactant for AMA. To focus on the chemical characteristics requisite for binding of AMA to the xenobiotic-modified self-peptide, quantitative structure-activity relationship (QSAR) studies were performed using a panel of alkynoic compounds, including examination of the length of the carbon chain and the location of the triple bond in the identified mimotope. Analyses of octynamides that varied in the position of the triple bond demonstrated that only the 2-octynamide reacted strongly with PBC sera. Furthermore, among 2-alkynamides with varying carbon chain length, 2-octyn-, 2-nonyn- (particularly) and 2-decynamide exhibited the highest reactivity. Thus, an optimal chemical structure of the xenobiotically modified epitope recognized by AMA-positive PBC sera is provided by 2-nonynoic acid. The methyl ester of this compound is ranked 2324th out of 12,945 compounds to which there is occupational exposure, with an 80% female prevalence due to its use in cosmetic products. Our findings illustrate an unusual polyreactivity of anti-PDC-E2 and support the idea of epitope mimicry in the genesis of this autoantibody and perhaps of PBC itself. (c) 2006 Elsevier Ltd. All rights reserved.