Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160, United States.
Chem Res Toxicol. 2011 May 16;24(5):744-51. doi: 10.1021/tx200033v. Epub 2011 Apr 21.
A predominant pathway of xenobiotic-induced toxicity is initiated by bioactivation. Characterizing reactive intermediates will provide information on the structure of reactive species, thereby defining a potential bioactivation mechanism. Because most reactive metabolites are not stable, it is difficult to detect them directly. Reactive metabolites can form adducts with trapping reagents, such as glutathione, which makes the reactive metabolites detectable. However, it is challenging to "fish" these adducts out from a complex biological matrix, especially for adducts generated via uncommon metabolic pathways. In this regard, we developed a novel approach based upon metabolomic technologies to screen trapped reactive metabolites. The bioactivation of pulegone, acetaminophen, and clozapine were reexamined by using this metabolomic approach. In all these cases, a large number of trapped reactive metabolites were readily identified. These data indicate that this metabolomic approach is an efficient tool to profile xenobiotic bioactivation.
一种主要的外源化学物诱导毒性的途径是通过生物活化作用引发的。描述反应性中间产物将提供关于反应性物质结构的信息，从而定义潜在的生物活化机制。由于大多数反应性代谢物不稳定，因此很难直接检测到它们。反应性代谢物可以与捕获试剂（如谷胱甘肽）形成加合物，从而使反应性代谢物能够被检测到。然而，从复杂的生物基质中“钓出”这些加合物是具有挑战性的，特别是对于通过不常见的代谢途径生成的加合物。在这方面，我们开发了一种基于代谢组学技术的新方法来筛选捕获的反应性代谢物。我们使用这种代谢组学方法重新研究了薄荷酮、对乙酰氨基酚和氯氮平的生物活化。在所有这些情况下，都很容易鉴定出大量的捕获的反应性代谢物。这些数据表明，这种代谢组学方法是一种有效的研究外源化学物生物活化的工具。
