摘要
在过去的几十年中,酶与解毒相关,并能帮助消除体内的外来化学物质,偶尔会产生高度活性代谢毒物这一观点已经非常清晰明了。为减少后期临床失败的概率或市场退出率,可能导致药物相互作用或毒性的关键代谢过程逐渐被重视。在活性代谢物的检测和了解结构活性关系取得了重大进展。现在人们普遍认为与某些官能团如苯胺类化合物、醌类、肼、呋喃、噻吩、acylpropionic酸、炔烃含有这些“结构性警报”的化合物比不包含的化合物形成活性代谢产物的风险更大。活性代谢物的检测通常是用在体外实验中,质谱的发展使检测变得更加灵敏。随着越来越多化合物形成的活性代谢产物已确定。大部分的重点已经从检测转变到毒理学的评价。然而有过多的化合物代谢形成活性代谢物导致肝毒性,严重的皮肤毒性如毒性内皮细胞坏死松解症和史蒂文的约翰逊综合症。 基于体外毒性测试的预测方法已经不能满足需求。在本文我们试图总结评估活性代谢物的实验方法。
关键词: 生物活化,细胞色素P450,肝毒性,活性代谢物
Current Medicinal Chemistry
Title:Gauging Reactive Metabolites in Drug-Induced Toxicity
Volume: 22 Issue: 4
Author(s): Marsha R. Eno and Michael D. Cameron
Affiliation:
关键词: 生物活化,细胞色素P450,肝毒性,活性代谢物
摘要: Over the past decades, it has become abundantly clear that enzymes evolved to detoxify and eliminate foreign chemicals from the body, occasionally generate highly reactive metabolites which have toxicological implications. To decrease the probability of late clinical failure or market withdrawal, there has been an increased prioritization on understanding key metabolic processes that might cause drug interactions or toxicities. Significant advances have been made in the detection of reactive metabolites and in understanding the structure activity relationship. It is now widely accepted that compounds with certain functional groups such as anilines, quinones, hydrazines, thiophenes, furans, acylpropionic acids, and alkynes have a much greater associated risk towards formation of reactive metabolites than compounds that do not contain such “structural alerts”. Detection of reactive metabolites is usually done with in vitro assays, which have become more sensitive with advances in mass spectrometry. As an increasingly large number of compounds that form reactive metabolites have been identified, much of the focus has shifted from detection to evaluation of toxicological implication. While there is a disproportionate number of compounds metabolized to reactive metabolites that are associated with drug-induced hepatotoxicity and serious skin toxicities such as toxic endothelial necrolysis and Steven’s Johnson syndrome, attempts to predict toxicity based on in vitro testing have been discouraging. In this review we attempt to summarize the experimental options available to evaluate reactive metabolites.
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Cite this article as:
Marsha R. Eno and Michael D. Cameron , Gauging Reactive Metabolites in Drug-Induced Toxicity, Current Medicinal Chemistry 2015; 22 (4) . https://dx.doi.org/10.2174/0929867321666140826113520
DOI https://dx.doi.org/10.2174/0929867321666140826113520 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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