Vol. 31, Issue 4, 432-438, April 2003

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

Division of Pharmacy, Chiba University Hospital Inohana, Chuo-ku, Chiba, Japan (H.N., N.A., H.N., M.K.); Graduate School of Pharmaceutical Science, Chiba University Yayoi-cho, inage-ku, Chiba, Japan (N.T., I.I.); and Division of Pharmacy, Shinsyu University Hospital Asahi, Matsumoto, Japan (S.O.)

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, 17-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 K_m and increase in V_max for CYP3A7-mediated CBZ 10,11-epoxidation, whereas DHEA-S 16-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.