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, Mitsukazu Kitada

Research output: Contribution to journalArticle

33 Citations (Scopus)

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 in Km and increase in Vmax 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.

Original languageEnglish
Pages (from-to)432-438
Number of pages7
JournalDrug Metabolism and Disposition
Volume31
Issue number4
DOIs
Publication statusPublished - Apr 1 2003
Externally publishedYes

Fingerprint

Cytochrome P-450 CYP3A
Epoxidation
Carbamazepine
Steroids
Dehydroepiandrosterone
Dehydroepiandrosterone Sulfate
Sulfates
Androstenedione
Pregnenolone
Hydroxylation
Kinetics
Liver Microsomes
Sigmoid Colon
Enzymes
Metabolism
Liver

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

CYP3A4 and CYP3A7-mediated carbamazepine 10,11-epoxidation are activated by differential endogenous steroids. / Nakamura, Hiroyoshi; Torimoto, Nao; Ishii, Itsuko; Ariyoshi, Noritaka; Nakasa, Hiromitsu; Ohmori, Shigeru; Kitada, Mitsukazu.

In: Drug Metabolism and Disposition, Vol. 31, No. 4, 01.04.2003, p. 432-438.

Research output: Contribution to journalArticle

Nakamura, Hiroyoshi ; Torimoto, Nao ; Ishii, Itsuko ; Ariyoshi, Noritaka ; Nakasa, Hiromitsu ; Ohmori, Shigeru ; Kitada, Mitsukazu. / CYP3A4 and CYP3A7-mediated carbamazepine 10,11-epoxidation are activated by differential endogenous steroids. In: Drug Metabolism and Disposition. 2003 ; Vol. 31, No. 4. pp. 432-438.
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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 in Km and increase in Vmax 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.",
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T1 - CYP3A4 and CYP3A7-mediated carbamazepine 10,11-epoxidation are activated by differential endogenous steroids

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AU - Ohmori, Shigeru

AU - Kitada, Mitsukazu

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