DMD Large equally mixed donor pool

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Drug Metabolism and Disposition Fast Forward
First published on July 24, 2008; DOI: 10.1124/dmd.108.021493

0090-9556/08/3611-2234-2243$20.00
DMD 36:2234-2243, 2008

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.108.021493v1
dmd.108.021493v2
36/11/2234    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sridar, C.
Right arrow Articles by Hollenberg, P. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sridar, C.
Right arrow Articles by Hollenberg, P. F.

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

Chitra Sridar, Ute M. Kent, Kate Noon, Alecia McCall, Bill Alworth, Maryam Foroozesh, and Paul F. Hollenberg

Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (C.S., U.M.K., K.N., P.F.H.); Department of Chemistry, Tulane University, New Orleans, Louisiana (B.A.); and Department of Chemistry, Xavier University of Louisiana, New Orleans, Louisiana (A.M.C., M.F.)

The abilities of 7-coumarin propargyl ether (CPE) and 7-(4-trifluoromethyl)coumarin propargyl ether (TFCPE) to act as mechanism-based inactivators of P450 3A4 and 3A5 in the reconstituted system have been investigated using 7-benzyloxy-4-(trifluoromethyl)coumarin (BFC) and testosterone as probes. CPE inhibited the BFC O-debenzylation activity of P450 3A4 in a time-, concentration-, and NADPH-dependent manner characteristic of a mechanism-based inactivator with a half-maximal inactivation (KI) of 112 µM, a maximal rate of inactivation (kinact) of 0.05 min-1, and a t1/2 of 13.9 min. Similarly, TFCPE inhibited the BFC O-debenzylation activity of P450 3A4 in a time-, concentration-, and NADPH-dependent manner with a KI of 14 µM, a kinact of 0.04 min-1, and a t1/2 of 16.5 min. Parallel losses of P450 3A4 enzymatic activity and heme were observed with both compounds as measured by high-performance liquid chromatography and reduced CO spectra. Interestingly, neither compound inhibited the BFC O-debenzylation activity of P450 3A5. Reactive intermediates of CPE and TFCPE formed by P450 3A4 were trapped with glutathione, and the resulting adducts were identified using tandem mass spectral analysis. Metabolism studies using TFCPE resulted in the identification of a single metabolite that is formed by P450 3A4 but not by P450 3A5 and that may play a role in the mechanism-based inactivation.

Address correspondence to: Dr. Paul F. Hollenberg, Department of Pharmacology, The University of Michigan, 1150 West Medical Center Dr., Ann Arbor, MI 48109-5632. E-mail: phollen{at}umich.edu




This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
H.-l. Lin, H. Zhang, K. R. Noon, and P. F. Hollenberg
Mechanism-Based Inactivation of CYP2B1 and Its F-Helix Mutant by Two tert-Butyl Acetylenic Compounds: Covalent Modification of Prosthetic Heme Versus Apoprotein
J. Pharmacol. Exp. Ther., November 1, 2009; 331(2): 392 - 403.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2008 by the American Society for Pharmacology and Experimental Therapeutics.