Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: Prominent roles for CYP3A and CYP2D6
Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: Prominent roles for CYP3A and CYP2D6
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DOI：
10.1124/jpet.104.065607
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发表时间：
2004-09-01
影响因子：
3.5
通讯作者：
Flockhart, DA
中科院分区：
文献类型：
--
作者：
Desta, Z;Ward, BA;Flockhart, DA
我们在人肝微粒体中进行了全面的动力学、抑制和相关性分析，并在表达的人细胞色素P450（P450）中进行了实验，以确定他莫昔芬（TAM）和P450在治疗相关浓度下催化这些反应的主要和次要代谢途径。在定量上，由CYP 3A 4/5催化的N-去甲基-TAM形成是TAM的主要初级代谢产物;由CYP 2D 6（和其他P450）催化的4-羟基-TAM形成是次要途径。其他次要初级代谢产物包括α-、3-和4 '-羟基TAM和一种未鉴别代谢产物（M-I），主要分别由CYP 3A 4、CYP 3A 5、CYP 2B 6/2C 19和CYP 3A 4催化。以N-去甲基和4-羟基-TAM为中间底物研究TAM的次级代谢。N-去甲基-TAM主要生物转化为α-羟基N-去甲基、N-去二甲基-和4-羟基N-去甲基-TAM（内昔芬），而4-羟基-TAM转化为3，4-二羟基TAM和内昔芬。除了N-去甲基-TAM向内昔芬的生物转化仅由CYP 2D 6催化外，所有其他N-去甲基-和4-羟基TAM生物转化途径主要由CYP 3A亚家族催化。TAM及其主要代谢产物主要通过CYP 3A和CYP 2D 6进行广泛氧化，生成表现出一系列药理学作用的代谢产物。由遗传多态性和药物相互作用引起的这些P450的可变活性可能会改变体内TAM效应的平衡。
We performed comprehensive kinetic, inhibition, and correlation analyses in human liver microsomes and experiments in expressed human cytochromes P450 (P450s) to identify primary and secondary metabolic routes of tamoxifen (TAM) and the P450s catalyzing these reactions at therapeutically relevant concentrations. N-Desmethyl-TAM formation catalyzed by CYP3A4/5 was quantitatively the major primary metabolite of TAM; 4-hydroxy-TAM formation catalyzed by CYP2D6 ( and other P450s) represents a minor route. Other minor primary metabolites include alpha -, 3-, and 4'-hydroxyTAM and one unidentified metabolite (M-I) and were primarily catalyzed by CYP3A4, CYP3A5, CYP2B6/2C19, and CYP3A4, respectively. TAM secondary metabolism was examined using N-desmethyland 4-hydroxy-TAM as intermediate substrates. N-Desmethyl-TAM was predominantly biotransformed to alpha-hydroxy N-desmethyl, N-didesmethyl-, and 4-hydroxy N-desmethyl-TAM (endoxifen), whereas 4-hydroxy-TAM was converted to 3,4-dihydroxyTAM and endoxifen. Except for the biotransformation of N-desmethyl-TAM to endoxifen, which was exclusively catalyzed by CYP2D6, all other routes of N-desmethyl- and 4-hydroxyTAM biotransformation were catalyzed predominantly by the CYP3A subfamily. TAM and its primary metabolites undergo extensive oxidation, principally by CYP3A and CYP2D6 to metabolites that exhibit a range of pharmacological effects. Variable activity of these P450s, brought about by genetic polymorphisms and drug interactions, may alter the balance of TAM effects in vivo.