An epoxidation mechanism of carbamazepine by CYP3A4
An epoxidation mechanism of carbamazepine by CYP3A4
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DOI：
10.1016/j.bmc.2008.03.023
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发表时间：
2008-05-01
影响因子：
3.5
通讯作者：
Hoshino, Tyuji
中科院分区：
文献类型：
--
作者：
Hata, Masayuki;Tanaka, Yoshikazu;Hoshino, Tyuji
人细胞色素P3A4催化卡马西平的10，11-环氧化反应。然而，环氧化物在势能方面不如六元芳环的氢氧化物稳定。为了阐明CYP3A4产生如此不利于能量的化合物的原因，通过理论计算研究了该化合物环氧化CBZ的反应机理。该反应包括两个基本过程，其中两个C-O键是逐步生成的。在密度泛函(DFT)(B3LYP/6-31G**)水平上，确定了第一步反应的反应速率，其反应活化能为21.3kcal/mol。10，11-环氧化第一步的活化能低于芳环羟化的活化能。因此，10，11-环氧化比芳环羟基化更有可能，只生成10，11-环氧化物。(C)2008爱思唯尔有限公司。保留所有权利。
Human CYP3A4 catalyzes the 10,11-epoxidation of carbamazepine (CBZ). However, the epoxide is less stable in terms of potential energy than hydroxides of the six-membered aromatic ring. To clarify the reason why CYP3A4 produces such an energetically unfavorable compound, the mechanism of epoxidation of CBZ by CYP3A4 was investigated by theoretical calculations. The reaction consisted of two elementary processes in which two C-O bonds were generated stepwise. The rate-determining step was the first one and the activation energy was 21.3 kcal/mol at the DFT (B3LYP/6-31G**) level. The activation energy level of the first step of the 10,11-epoxidation was lower than that of the hydroxylation of the aromatic ring. For this reason, 10,11-epoxidation is more probable than hydroxylation of the aromatic ring, and only 10,11-epoxide is formed. (C) 2008 Elsevier Ltd. All rights reserved.