Direct Interaction between Substrates and Endogenous Steroids in the Active Site May Change the Activity of Cytochrome P450 3A4
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- 作者：Nao Torimoto ; Itsuko Ishii ; Masayuki Hata ; Hiroyoshi Nakamura ; Hiroshi Imada ; Noritaka Ariyoshi ; Shigeru Ohmori ; Takashi Igarashi ; and Mitsukazu Kitada
- 刊名：Biochemistry
- 出版年：2003
- 出版时间：December 30, 2003
- 年：2003
- 卷：42
- 期：51
- 页码：15068 - 15077
- 全文大小：391K
- 年卷期：v.42,no.51(December 30, 2003)
- ISSN：1520-4995
文摘
CYP3A4 exhibits unusual kinetic characteristics that result from the metabolism of multiplesubstrate including endogenous steroids and some drugs that coexist at the active site. To clarify themechanism of the effect of endogenous steroids on the drug metabolism, the interaction between substrates,nevirapine (NVP) and carbamazepine (CBZ), and endogenous steroids was investigated by theoreticalcalculations. When the activities of NVP 2-hydroxylation and CBZ 10,11-epoxidation by expressedCYP3A4 were measured in the presence of steroids, NVP 2-hydroxylation was found to be remarkablyincreased by aldosterone and inhibited by estradiol. CBZ 10,11-epoxidation was increased by androstenedione. Three-dimensional computer modeling has shown that the active site of CYP3A4 is especiallylarge, permitting access of two substrate molecules. The interactions between NVP and aldosterone andbetween CBZ and androstenedione were estimated by theoretical calculations assuming the substrate andsteroids to be present in the active site at the same time. It was shown that NVP or CBZ would be stablyfixed close to the oxygen atom at the sixth ligand of heme by interaction with steroids, suggesting thatNVP and CBZ may be hydroxylated more easily due to the interaction with steroids. Estradiol was alsoexpected to interact with NVP via a 
/ interaction between a benzene ring, in which the NVPhydroxylation site is located, and a benzene ring of estradiol, suggested to inhibit the reaction. Fromthese results, interactions between the substrate and endogenous steroids in the active site may changethe activity of CYP3A4.
/ interaction between a benzene ring, in which the NVPhydroxylation site is located, and a benzene ring of estradiol, suggested to inhibit the reaction. Fromthese results, interactions between the substrate and endogenous steroids in the active site may changethe activity of CYP3A4.