Differential Oxidation of Mifepristone by Cytochromes P450 3A4 and 3A5: Selective Inactivation of P450 3A4
The principal enzyme involved in the oxidation of mifepristone is cytochrome P450 3A4 (CYP3A4), which undergoes mechanism-based inactivation by the drug. However, no information is available on the interaction with CYP3A5, the second most abundant CYP3A enzyme in adult human liver. Oxidation of mife...
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Published in | Drug metabolism and disposition Vol. 30; no. 9; pp. 985 - 990 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
American Society for Pharmacology and Experimental Therapeutics
01.09.2002
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Subjects | |
Online Access | Get full text |
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Summary: | The principal enzyme involved in the oxidation of mifepristone is cytochrome P450 3A4 (CYP3A4), which undergoes mechanism-based
inactivation by the drug. However, no information is available on the interaction with CYP3A5, the second most abundant CYP3A
enzyme in adult human liver. Oxidation of mifepristone by recombinant CYP3A4 produced mono- and didemethylated products and
one C-hydroxylated metabolite, as reported previously. However, CYP3A5 produced only the demethylated metabolites. The apparent
V max and K M values for formation of the monodemethylated product by CYP3A4 and CYP3A5 were 46 and 30 nmol/min/nmol P450, and 36 and 16
μM, respectively. Unlike CYP3A4, CYP3A5 was not inactivated by mifepristone. The basis of this differential susceptibility
was explored using site-directed mutants in which a CYP3A4 residue was converted to its 3A5 counterpart. Surprisingly, none
of these replacements caused a significant decrease in CYP3A4 inactivation by mifepristone. Examination of selected CYP3A4
mutants at 20 other positions indicated that the relative formation rate of the C-hydroxylated product could not account for
the differential susceptibility of CYP3A4 and 3A5. Together these results indicate that mifepristone fails to orient itself
in the CYP3A5 active site in such a way that its propylenic group is accessible for oxidation, thus rendering CYP3A5 unable
to produce the C-hydroxylated product or putative ketene that leads to enzyme inactivation. Identification of mifepristone
as a selective mechanism-based inactivation of CYP3A4 may be very useful in distinguishing between the two major CYP3A enzymes
collectively responsible for the oxidative metabolism of over half of the drugs currently in use. |
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ISSN: | 0090-9556 1521-009X |
DOI: | 10.1124/dmd.30.9.985 |