Cohen S D, Pumford N R, Khairallah E A, Boekelheide K, Pohl L R, Amouzadeh H R, Hinson J A
Department of Pharmaceutical Sciences, University of Connecticut, Storrs 06269-2092, USA.
Toxicol Appl Pharmacol. 1997 Mar;143(1):1-12. doi: 10.1006/taap.1996.8074.
Protein covalent binding by xenobiotic metabolites has long been associated with target organ toxicity but mechanistic involvement of such binding has not been widely demonstrated. Modern biochemical, molecular, and immunochemical approaches have facilitated identification of specific protein targets of xenobiotic covalent binding. Such studies have revealed that protein covalent binding is not random, but rather selective with respect to the proteins targeted. Selective binding to specific cellular target proteins may better correlate with toxicity than total protein covalent binding. Current research is directed at characterizing and identifying the targeted proteins and clarifying the effect of such binding on their structure, function, and potential roles in target organ toxicity. The approaches employed to detect and identify the tartgeted proteins are described. Metabolites of acetaminophen, halothane, and 2,5-hexanedione form covalently bound adducts to recently identified protein targets. The selective binding may influence homeostatic or other cellular responses which in turn contribute to drug toxicity, hypersensitivity, or autoimmunity.
外源性代谢物与蛋白质的共价结合长期以来一直与靶器官毒性相关，但这种结合的机制尚未得到广泛证实。现代生物化学、分子和免疫化学方法有助于鉴定外源性共价结合的特定蛋白质靶点。此类研究表明，蛋白质共价结合并非随机发生，而是针对特定的蛋白质具有选择性。与总蛋白质共价结合相比，与特定细胞靶蛋白的选择性结合可能与毒性有更好的相关性。当前的研究旨在表征和鉴定靶蛋白，并阐明这种结合对其结构、功能以及在靶器官毒性中的潜在作用的影响。文中描述了用于检测和鉴定靶蛋白的方法。对乙酰氨基酚、氟烷和2,5 -己二酮的代谢物会与最近鉴定出的蛋白质靶点形成共价结合加合物。这种选择性结合可能会影响体内稳态或其他细胞反应，进而导致药物毒性、超敏反应或自身免疫。
