![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 30, Issue 9, 985-990, September 2002
Department of Pharmacology and Toxicology, University of Texas
Medical Branch, Galveston, Texas (K.K.K., Y.Q.H., J.R.H.); Department
of Cellular and Molecular Pharmacology, Department of Pharmaceutical
Chemistry, Department of Biopharmaceutical Sciences, and the Liver
Center, University of California, San Francisco, California (M.A.C.)
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 Vmax and
KM 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.
This article has been cited by other articles:
|
|
 |
|
  H.-l. Lin, H. Zhang, and P. F. Hollenberg Metabolic Activation of Mifepristone [RU486; 17{beta}-Hydroxy-11{beta}-(4-dimethylaminophenyl)-17{alpha}-(1-propynyl)-estra-4,9-dien-3-one] by Mammalian Cytochromes P450 and the Mechanism-Based Inactivation of Human CYP2B6 J. Pharmacol. Exp. Ther., April 1, 2009; 329(1): 26 - 37. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Sridar, U. M. Kent, K. Noon, A. McCall, B. Alworth, M. Foroozesh, and P. F. Hollenberg Differential Inhibition of Cytochromes P450 3A4 and 3A5 by the Newly Synthesized Coumarin Derivatives 7-Coumarin Propargyl Ether and 7-(4-Trifluoromethyl)coumarin Propargyl Ether Drug Metab. Dispos., November 1, 2008; 36(11): 2234 - 2243. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Obligacion, M. Murray, and I. Ramzan Drug-Metabolizing Enzymes and Transporters: Expression in the Human Prostate and Roles in Prostate Drug Disposition J Androl, March 1, 2006; 27(2): 138 - 150. [Full Text] [PDF]
|
|
|
|
 |
|
 L. K. Kamdem, F. Streit, U. M. Zanger, J. Brockmoller, M. Oellerich, V. W. Armstrong, and L. Wojnowski Contribution of CYP3A5 to the in Vitro Hepatic Clearance of Tacrolimus Clin. Chem., August 1, 2005; 51(8): 1374 - 1381. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Huang, Y. S. Lin, D. J. McConn II, J. C. Calamia, R. A. Totah, N. Isoherranen, M. Glodowski, and K. E. Thummel EVIDENCE OF SIGNIFICANT CONTRIBUTION FROM CYP3A5 TO HEPATIC DRUG METABOLISM Drug Metab. Dispos., December 1, 2004; 32(12): 1434 - 1445. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. McConn II, Y. S. Lin, K. Allen, K. L. Kunze, and K. E. Thummel DIFFERENCES IN THE INHIBITION OF CYTOCHROMES P450 3A4 AND 3A5 BY METABOLITE-INHIBITOR COMPLEX-FORMING DRUGS Drug Metab. Dispos., October 1, 2004; 32(10): 1083 - 1091. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Shen, J. F. Fitzloff, and C. S. Cook DIFFERENTIAL ENANTIOSELECTIVITY AND PRODUCT-DEPENDENT ACTIVATION AND INHIBITION IN METABOLISM OF VERAPAMIL BY HUMAN CYP3AS Drug Metab. Dispos., February 1, 2004; 32(2): 186 - 196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yamaguchi, K. K. Khan, Y. A. He, Y. Q. He, and J. R. Halpert TOPOLOGICAL CHANGES IN THE CYP3A4 ACTIVE SITE PROBED WITH PHENYLDIAZENE: EFFECT OF INTERACTION WITH NADPH-CYTOCHROME P450 REDUCTASE AND CYTOCHROME B5 AND OF SITE-DIRECTED MUTAGENESIS Drug Metab. Dispos., January 1, 2004; 32(1): 155 - 161. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
