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Vol. 288, Issue 2, 791-797, February 1999
Department of Pharmacology, University of Michigan, Ann Arbor,
Michigan (K.H., P.F.H.); and
Department of Pharmacokinetics and Drug
Metabolism, Parke-Davis Pharmaceutical Research, Warner-Lambert Co.,
Ann Arbor, Michigan (T.F.W.)
Mifepristone (RU486), an 11
-substituted nor-steroid containing a
17
-1-propynyl group used clinically as an antiprogestin agent for
medical abortions, was demonstrated to be a selective mechanism-based
inactivator of human cytochrome P-450-3A4 (CYP-3A4). The loss of
testosterone 6-hydroxylation activity was time- and concentration-dependent as well as requiring metabolism of mifepristone in a purified CYP-3A4 reconstituted system. The inactivation exhibited pseudofirst-order kinetics. The values for
KI and
kinactivation were 4.7 µM and 0.089 min
1, respectively. The reduced-CO spectrum of CYP-3A4
was decreased by 76%, whereas approximately 81% of the activity was
lost following incubation with mifepristone in the reconstituted system
in the presence of NADPH. However, the Soret peak of the inactivated CYP-3A4 was slightly increased. High-performance liquid
chromatography analysis of the incubation mixture showed that
the peak containing the heme dissociated from the inactivated CYP3A4
was almost identical with that seen for the 
NADPH control. Covalent
binding of [3H]mifepristone to apoCYP3A4 was demonstrated
by SDS-PAGE and high-pressure liquid chromatography analyses of the
reconstituted system containing CYP-3A4, NADPH-CYP reductase,
cytochrome b5 and lipids in the presence of
NADPH. The stoichiometry was determined to be approximately 1 mol of
mifepristone bound per 1 mol of CYP-3A4 inactivated. Therefore, the
mechanism of inactivation of CYP-3A4 by mifepristone involves
irreversible modification of the apoprotein at the enzyme active site
instead of being the result of heme adduct formation or heme
fragmentation. Mifepristone exhibits selectivity for CYP-3A4 as
evidenced by the fact that it did not show mechanism-based inactivation
of CYPs 1A, 2B, 2D6, and 2E1, although a competitive inhibition of CYP
2B1 and 2D6 was observed.
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