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Research ArticleArticle

CYP3A4 and CYP3A7-Mediated Carbamazepine 10,11-Epoxidation Are Activated by Differential Endogenous Steroids

Hiroyoshi Nakamura, Nao Torimoto, Itsuko Ishii, Noritaka Ariyoshi, Hiromitsu Nakasa, Shigeru Ohmori and Mitsukazu Kitada
Drug Metabolism and Disposition April 2003, 31 (4) 432-438; DOI: https://doi.org/10.1124/dmd.31.4.432
Hiroyoshi Nakamura
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Nao Torimoto
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Itsuko Ishii
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Noritaka Ariyoshi
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Hiromitsu Nakasa
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Shigeru Ohmori
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Mitsukazu Kitada
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Abstract

Recently, we reported that several endogenous steroids affect CYP3A4-mediated drug metabolism, using human adult liver microsomes as an enzyme source. Especially, carbamazepine (CBZ) 10,11-epoxidation is activated by androstenedione (AND). In the present studies, we investigated the effects of endogenous steroids on the activity of CBZ 10,11-epoxidation by expressed CYP3A4 and CYP3A7. When expressed CYP3A4 was used as an enzyme source, the addition of AND to the reaction mixture also caused a drastic increase in the activity of CBZ 10,11-epoxidase, and resulted in a change in the kinetics from sigmoid to Michaelis-Menten type. On the other hand, expressed CYP3A7-mediated CBZ 10,11-epoxidation was activated by sulfate conjugate steroids, such as pregnenolone 3-sulfate, 17α-hydroxypregnenolone 3-sulfate, and dehydroepiandrosterone 3-sulfate (DHEA-S), whereas the unconjugated form corresponding to these three steroids did not activate the reaction. Especially, DHEA-S was found to be a potent activator of CBZ 10,11-epoxidation by expressed CYP3A7. The kinetic character of CBZ 10,11-epoxidation by CYP3A7 is Michaelis-Menten type regardless of the presence of DHEA-S. The presence of DHEA-S caused a decrease inKm and increase inVmax for CYP3A7-mediated CBZ 10,11-epoxidation, whereas DHEA-S 16α-hydroxylation was not affected by the coexistence of CBZ. In conclusion, CYP3A4 and CYP3A7-mediated CBZ 10,11-epoxidations are activated by different types of endogenous steroids. This is the first report regarding CYP3A7 cooperativity.

Footnotes

  • Abbreviations used are::
    P450s
    cytochrome P450s
    AND
    androstendione
    DHEA
    dehydroepiandrosterone
    HPLC
    high-performance liquid chromatography
    DHEA-S
    dehydroepiandrosterone 3-sulfate
    EST
    estradiol
    • Received November 4, 2002.
    • Accepted December 20, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (4)
Drug Metabolism and Disposition
Vol. 31, Issue 4
1 Apr 2003
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Research ArticleArticle

CYP3A4 and CYP3A7-Mediated Carbamazepine 10,11-Epoxidation Are Activated by Differential Endogenous Steroids

Hiroyoshi Nakamura, Nao Torimoto, Itsuko Ishii, Noritaka Ariyoshi, Hiromitsu Nakasa, Shigeru Ohmori and Mitsukazu Kitada
Drug Metabolism and Disposition April 1, 2003, 31 (4) 432-438; DOI: https://doi.org/10.1124/dmd.31.4.432

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Research ArticleArticle

CYP3A4 and CYP3A7-Mediated Carbamazepine 10,11-Epoxidation Are Activated by Differential Endogenous Steroids

Hiroyoshi Nakamura, Nao Torimoto, Itsuko Ishii, Noritaka Ariyoshi, Hiromitsu Nakasa, Shigeru Ohmori and Mitsukazu Kitada
Drug Metabolism and Disposition April 1, 2003, 31 (4) 432-438; DOI: https://doi.org/10.1124/dmd.31.4.432
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