Mechanism-based inactivation of cytochrome P-450-3A4 by mifepristone (RU486).

Article Details

Citation

He K, Woolf TF, Hollenberg PF

Mechanism-based inactivation of cytochrome P-450-3A4 by mifepristone (RU486).

J Pharmacol Exp Ther. 1999 Feb;288(2):791-7.

PubMed ID
9918590 [ View in PubMed
]
Abstract

Mifepristone (RU486), an 11beta-substituted nor-steroid containing a 17alpha-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 6beta-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 microM 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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
MifepristoneCytochrome P450 2D6ProteinHumans
Unknown
Inhibitor
Details
Drug Interactions
DrugsInteraction
Bromocriptine
Mifepristone
The serum concentration of Bromocriptine can be increased when it is combined with Mifepristone.
Cabergoline
Mifepristone
The serum concentration of Cabergoline can be increased when it is combined with Mifepristone.
Dihydroergocornine
Mifepristone
The serum concentration of Dihydroergocornine can be increased when it is combined with Mifepristone.
Dihydroergocristine
Mifepristone
The serum concentration of Dihydroergocristine can be increased when it is combined with Mifepristone.
Dihydroergotamine
Mifepristone
The serum concentration of Dihydroergotamine can be increased when it is combined with Mifepristone.