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Vol. 31, Issue 4, 432-438, April 2003
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
Km and increase in
Vmax 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.
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