Human cytochrome P450 3A4: enzymatic properties of a purified recombinant fusion protein containing NADPH-P450 reductase.
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- M S Shet
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas 75235-9038.
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- C W Fisher
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas 75235-9038.
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- P L Holmans
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas 75235-9038.
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- R W Estabrook
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas 75235-9038.
抄録
<jats:p>Human cytochrome P450 3A4 is recognized as the catalyst for the oxygen-dependent metabolism of a diverse group of medically important chemicals, including the immunosuppressive agent cyclosporin; macrolide antibiotics, such as erythromycin; drugs such as benzphetamine, nifedipine, and cocaine; and steroids; such as cortisol and testosterone to name but a few. We have engineered the cDNA for human cytochrome P450 3A4 by linkage to the cDNA for the rat or human flavoprotein, NADPH-P450 reductase (NADPH:ferrihemoprotein oxidoreductase, EC 1.6.2.4). An enzymatically active fusion protein (rF450[mHum3A4/mRatOR]L1) has been expressed at high levels in Escherichia coli and purified to homogeneity. Enzymatic studies show a requirement for lipid, detergent, and cytochrome b5 for the 6 beta-hydroxylation of steroids and the N-oxidation of nifedipine. In contrast, these additions are not required for the N-demethylation of erythromycin or benzphetamine. A spectrophotometrically detectable metabolite complex of P450 3A4 is formed during the metabolism of triacetyloleandomycin, and this has a pronounced inhibitory effect on the metabolism of both testosterone and erythromycin. These results relate to the interpretation of current methods used to assess the in vivo activity of P450 3A4.</jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 90 (24), 11748-11752, 1993-12-15
Proceedings of the National Academy of Sciences
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詳細情報 詳細情報について
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- CRID
- 1364233270896757376
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- NII論文ID
- 30016295425
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- ISSN
- 10916490
- 00278424
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- データソース種別
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