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 August 31, 2005; DOI: 10.1124/dmd.105.006031

0090-9556/05/3312-1837-1844$20.00
DMD 33:1837-1844, 2005

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.105.006031v1
33/12/1837    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 Regal, K. A.
Right arrow Articles by Nelson, S. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Regal, K. A.
Right arrow Articles by Nelson, S. D.

OXIDATION OF CAFFEINE BY CYP1A2: ISOTOPE EFFECTS AND METABOLIC SWITCHING

Kelly A. Regal1, Kent L. Kunze, Raimund M. Peter2, and Sidney D. Nelson

Department of Medicinal Chemistry, University of Washington, Seattle, Washington

Caffeine (1,3,7-trimethylxanthine) has previously been shown to undergo metabolic switching in vivo when the N-1 or the N-7 methyl groups were trideuteromethylated [Horning et al. (1976) Proceedings of the Second International Conference on Stable Isotopes, pp 41–54]. We have examined the effect of replacing the N-3 methyl group with a trideuteromethyl group. The corresponding isotope effects can then be used to distinguish the kinetic mechanism by which four primary metabolites can be formed from one substrate by one cytochrome P450 (P450). We have synthesized 3-CD3-caffeine and 3-CD3-7-CD3-caffeine as well as trideuteromethylated analogs of each of the in vitro metabolites formed by cytochrome P4501A2. The observed competitive isotope effects for the metabolites, which do not result from deuterium abstraction (theobromine, theophylline), demonstrate that the nondissociative mechanism applies to caffeine metabolism by cytochrome P4501A2. Thus, there must be equilibration of the kinetically distinguishable activated P450-substrate complexes at rates competitive with hydrogen abstraction. The true isotope effects for the N-3 demethylation of caffeine were derived from the ratios of the amount of paraxanthine relative to the amount of theobromine or theophylline. The resultant ratios indicate that these isotope effects are essentially intrinsic. Observation of the isotope effects on N-3 demethylation was facilitated by branching to the minor in vitro metabolites as well as water formation. Product release is not rate-limiting for this system.

Address correspondence to: Dr. Sidney Nelson, Dept. of Medicinal Chemistry, University of Washington School of Pharmacy, Box 357610, Seattle, WA 98195-7631. E-mail: sidnels{at}u.washington.edu




This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
T. S. Dowers and J. P. Jones
KINETIC ISOTOPE EFFECTS IMPLICATE A SINGLE OXIDANT FOR CYTOCHROME P450-MEDIATED O-DEALKYLATION, N-OXYGENATION, AND AROMATIC HYDROXYLATION OF 6-METHOXYQUINOLINE
Drug Metab. Dispos., August 1, 2006; 34(8): 1288 - 1290.
[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 © 2005 by the American Society for Pharmacology and Experimental Therapeutics.