Theoretical calculation of triazolam hydroxylation and endogenous steroid inhibition in the active site of CYP3A4.
Theoretical calculation of triazolam hydroxylation and endogenous steroid inhibition in the active site of CYP3A4.
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CYP3A4 活性位点三唑仑羟基化和内源类固醇抑制的理论计算。
DOI：
10.1016/j.bbapap.2006.11.009
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
M. Kitada
中科院分区：
文献类型：
--
作者：
Nao Torimoto;I. Ishii;M. Hata;Yukari Kobayashi;Hiroyoshi Nakamura;N. Ariyoshi;M. Kitada
CYP 3A 4具有不寻常的动力学特征，因为它具有大的活性位点。当三唑仑浓度大于60 μM时，CYP 3A 4产生的4-羟基三唑仑多于α-羟基三唑仑，不同甾体对系统的抑制作用不同。为了澄清这些有趣的观察，底物和底物/类固醇之间的相互作用进行了研究，通过理论计算。当两个三唑仑分子对接到活性位点时，由于两个三唑仑分子之间的相互作用，O原子与4-羟基化位点之间的距离小于O原子与α-羟基化位点之间的距离。依地平抑制α-和4-羟基三唑仑形成50%。脱氢表雄酮（DHEA）抑制α-羟基化作用强于4-羟基三唑仑，而醛固酮则无此作用。当一个三唑仑分子和一个甾体分子同时对接时，雌二醇增加了O原子与两个羟基化位点之间的距离，DHEA只增加了O原子与α-羟基化位点之间的距离，而醛固酮不改变O原子与α-羟基化位点之间的距离。三唑仑羟基化位点的Fe-O-C相关角也变宽，距离也增加。这些发现表明，在活性位点的底物和底物/效应复合物的形成可能是决定CYP 3A 4的酶动力学参数的一个因素。
CYP3A4 has unusual kinetic characteristics because it has a large active site. CYP3A4 produced more 4-hydroxytriazolam than α-hydroxytriazolam at concentrations of more than 60 μM triazolam, and different steroids had different inhibitory effects on the system. To clarify these interesting observations, the interactions between substrate and substrate/steroid were investigated by theoretical calculations. When two triazolam molecules were docked into the active site, the distance between the O-atom and the 4-hydroxylated site was less than the distance to the α-hydroxylated site because of interaction between the two triazolam molecules. Estradiol inhibited both α- and 4-hydroxytriazolam formation by 50%. Dehydroepiandrosterone (DHEA) inhibited α-hydroxylation more than 4-hydroxytriazolam formation, whereas aldosterone had no effect. When one triazolam molecule and one steroid molecule were simultaneously docked, estradiol increased the distance between the O-atom and the two hydroxylated sites, DHEA only increased the distance between the O-atom and α-hydroxylated site, and aldosterone did not change the distances. The relevant angles of Fe–O–C in the hydroxylated site of triazolam also widened, together with increased distance. These findings indicate that formation of a substrate and substrate/effector complex in the active site may be a factor for determining the enzyme kinetic parameters of CYP3A4.
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DOI：
--
发表时间：
1994-07
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
T. Shimada;H. Yamazaki;M. Mimura;Y. Inui;F. Guengerich
通讯作者：
T. Shimada;H. Yamazaki;M. Mimura;Y. Inui;F. Guengerich
DOI：
10.1073/pnas.95.12.6636
发表时间：
1998-06-09
影响因子：
11.1
作者：
Harlow, GR;Halpert, JR
通讯作者：
Halpert, JR
影响因子：
2.9
作者：
Korzekwa, KR;Krishnamachary, N;Tracy, TS
通讯作者：
Tracy, TS
影响因子：
2.9
作者：
Ueng, YF;Kuwabara, T;Guengerich, FP
通讯作者：
Guengerich, FP
影响因子：
3.9
作者：
WAXMAN, DJ;ATTISANO, C;LAPENSON, DP
通讯作者：
LAPENSON, DP