Nonadditivity in human microsomal drug metabolism revealed in a study with coumarin 152, a polyspecific cytochrome P450 substrate.
Nonadditivity in human microsomal drug metabolism revealed in a study with coumarin 152, a polyspecific cytochrome P450 substrate.
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人类微粒体药物代谢中的非吸附性在一项研究中揭示了香豆素152（一种多元特异性的细胞色素P450底物）的研究。
DOI：
10.1080/00498254.2020.1775913
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Davydov DR
中科院分区：
文献类型：
--
作者：
Dangi B;Davydova NY;Vavilov NE;Zgoda VG;Davydov DR
为了研究细胞色素P450系统中的功能整合，我们对P450代谢底物7-二甲基氨基-4-三氟甲基香豆素（Coumarin 152，C152）进行了结构表征，建立了一种新的荧光探针。使用含有cDNA表达酶的微粒体表征了单个P450物质对C152的代谢。研究了人肝微粒体（HLM）中C152的代谢，该制剂定量测定了11种P450物质的含量。C152通过CYP 2B 6、CYP 3A 4、CYP 3A 5、CYP 2C 19、CYP 1A 2、CYP 2C 9和CYP 2C 8代谢，代谢顺序为转换递减。CYP 3A 4、CYP 2C 9和CYP 2C 8表现出的亲和力低于其他酶的特征亲和力。加和性假设表明，CYP 3A 4、CYP 2B 6和CYP 2C 19的参与率分别为84%、8%和0.2%。与此预测相反，抑制分析确定CYP 2C 19为主要的C152代谢酶。我们彻底表征C152的药物代谢的研究，在HLM和证明的比例投影方法的局限性，通过提供一个例子，其中的参与个别P450物种不能从他们的内容进行预测。
We closely characterized 7-Dimethylamino-4-trifluromethylcoumarin (Coumarin 152, C152), a substrate metabolized by multiple P450 species, to establish a new fluorogenic probe for the studies of functional integration in the cytochrome P450 ensemble, Scanning fluorescence spectroscopy and LC/MS-MS were used to characterize the products of N-demethylation of C152 and optimize their fluorometric detection. The metabolism of C152 by the individual P450 species was characterized using the microsomes containing cDNA-expressed enzymes. C152 metabolism in human liver microsomes (HLM) was studied in a preparation with quantified content of eleven P450 species C152 is metabolized by CYP2B6, CYP3A4, CYP3A5, CYP2C19, CYP1A2, CYP2C9, and CYP2C8 listed in the order of decreasing turnover. The affinities exhibited by CYP3A4, CYP2C9, and CYP2C8 were lower than those characteristic to the other enzymes. The presumption of additivity suggests the participation of CYP3A4, CYP2B6, and CYP2C19 to be 84, 8, and 0.2%, respectively. Contrary to this prediction, inhibitory analysis identified CYP2C19 as the principal C152-metabolizing enzyme. We thoroughly characterize C152 for the studies of drug metabolism in HLM and demonstrate the limitations of the proportional projection approach by providing an example, where the involvement of individual P450 species cannot be predicted from their content.
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影响因子：
2.3
作者：
Rendic S;Guengerich FP
通讯作者：
Guengerich FP
基因多态性和细胞色素P450含量对人肝微粒体代谢活动的影响有限
影响因子：
4.6
作者：
Gao, Na;Tian, Xin;Qiao, Hailing
通讯作者：
Qiao, Hailing
DOI：
10.1042/bcj20170543
发表时间：
2017-10-10
期刊：
The Biochemical journal
影响因子：
--
作者：
Davydov DR;Davydova NY;Rodgers JT;Rushmore TH;Jones JP
通讯作者：
Jones JP
影响因子：
2.9
作者：
Roberts, Arthur G.;Yang, Jing;Halpert, James R.;Nelson, Sidney D.;Thummel, Kenneth T.;Atkins, William M.
通讯作者：
Atkins, William M.
影响因子：
4.3
作者：
Davydov DR;Halpert JR
通讯作者：
Halpert JR