Selective inhibitors of cytochromes P450.
Selective inhibitors of cytochromes P450.
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DOI：
10.1006/taap.1994.1061
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发表时间：
1994-04
影响因子：
3.8
通讯作者：
J. Halpert;F. Guengerich;J. Bend;M. Correia
中科院分区：
文献类型：
--
作者：
J. Halpert;F. Guengerich;J. Bend;M. Correia
化合物在特定物种或器官中的解毒和生物活化之间的平衡高度依赖于所表达的不同形式的细胞色素P450（P450）的相对量和活性。因此，个别P450形式的催化特异性和调节的知识是至关重要的预测和/或合理化物种，菌株和异生物质代谢的个体差异，以及化合物之间的代谢相互作用，内源性和外源性。近年来出现的电池的异构体选择性化学抑制剂，可用于在体外和体内的实验动物和人类，大大促进了个别细胞色素P450负责特定的生物活化和解毒反应的鉴定。这些抑制剂中的许多是基于机制的，并且将其选择性归因于靶酶的代谢。这些化合物也被证明是有价值的探针的催化机制的细胞色素P450，用于确定氨基酸残基的重要性的各种功能的酶，用于评估的生理作用的P450衍生的氧化产物的内源性化合物，在化学诱导的模型急性肝卟啉症，并研究蛋白质周转。个体人细胞色素P450的异构体选择性无毒抑制剂的鉴定提高了出于治疗目的调节人药物代谢的真实的可能性。
The balance between detoxification and bioactivation of a compound in a particular species or organ is highly dependent on the relative amounts and activities of the different forms of cytochrome P450 (P450) that are expressed. Therefore, knowledge of the catalytic specificities and regulation of individual P450 forms is of paramount importance in predicting and/or rationalizing species, strain, and individual differences in xenobiotic metabolism as well as metabolic interactions between compounds, both endogenous and exogenous. The emergence in recent years of a battery of isoform-selective chemical inhibitors that can be used in vitro and in vivo in experimental animals and humans has greatly facilitated the identification of individual cytochromes P450 responsible for specific bioactivation and detoxification reactions. Many of these inhibitors are mechanism-based and owe their selectivity to metabolism by the target enzyme. Such compounds have also proven valuable as probes of the catalytic mechanism of cytochromes P450, for identifying amino acid residues of importance for the various functions of the enzyme, for assessing the physiological roles of P450-derived oxidation products of endogenous compounds, in chemical-induced models of acute hepatic porphyria, and for studying protein turnover. The identification of isoform-selective, nontoxic inhibitors of individual human cytochromes P450 raises the real possibility of modulation of human drug metabolism for therapeutic purposes.