PT  - JOURNAL ARTICLE
AU  - Nakamura, Hiroyoshi
AU  - Torimoto, Nao
AU  - Ishii, Itsuko
AU  - Ariyoshi, Noritaka
AU  - Nakasa, Hiromitsu
AU  - Ohmori, Shigeru
AU  - Kitada, Mitsukazu
TI  - CYP3A4 and CYP3A7-Mediated Carbamazepine 10,11-Epoxidation Are Activated by Differential Endogenous Steroids
AID  - 10.1124/dmd.31.4.432
DP  - 2003 Apr 01
TA  - Drug Metabolism and Disposition
PG  - 432--438
VI  - 31
IP  - 4
4099  - http://dmd.aspetjournals.org/content/31/4/432.short
4100  - http://dmd.aspetjournals.org/content/31/4/432.full
SO  - Drug Metab Dispos2003 Apr 01; 31
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics