DMD Simcyp

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


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
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 Zhang, W.
Right arrow Articles by Sellers, E. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhang, W.
Right arrow Articles by Sellers, E. M.

Vol. 29, Issue 6, 897-902, June 2001

Evaluation of Methoxsalen, Tranylcypromine, and Tryptamine as Specific and Selective CYP2A6 Inhibitors in Vitro

Wenjiang Zhang, Tansel Kilicarslan, Rachel F. Tyndale, and Edward M. Sellers

Departments of Pharmacology (W.Z., T.K., R.F.T., E.M.S.), Medicine (E.M.S.), and Psychiatry (E.M.S.), University of Toronto, Toronto, Canada; and Center for Addiction and Mental Health (R.F.T., E.M.S.), and Sunnybrook and Women's College Health Sciences Centre (E.M.S.), Toronto, Canada

CYP2A6 is the principle enzyme metabolizing nicotine to its inactive metabolite cotinine. In this study, the selective probe reactions for each major cytochrome P450 (P450) were used to evaluate the specificity and selectivity of the CYP2A6 inhibitors methoxsalen, tranylcypromine, and tryptamine in cDNA-expressing and human liver microsomes. Phenacetin O-deethylation (CYP1A2), coumarin 7-hydroxylation (CYP2A6), diclofenac 4'-hydroxylation (CYP2C9), omeprazole 5-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), 7-ethoxy-4-trifluoromethylcoumarin deethylation (CYP2B6), p-nitrophenol hydroxylation (CYP2E1), and omeprazole sulfonation (CYP3A4) were used as index reactions. Apparent Ki values for inhibition of P450s' (1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4) activities showed that tranylcypromine, methoxsalen, and tryptamine have high specificity and relative selectivity for CYP2A6. In cDNA-expressing microsomes, tranylcypromine inhibited CYP2A6 (Ki = 0.08 µM) with about 60- to 5000-fold greater potency relative to other P450s. Methoxsalen inhibited CYP2A6 (Ki = 0.8 µM) with about 3.5- 94-fold greater potency than other P450s, except for CYP1A2 (Ki = 0.2 µM). Tryptamine inhibited CYP2A6 (Ki = 1.7 µM) with about 6.5- 213-fold greater potency relative to other P450s, except for CYP1A2 (Ki = 1.7 µM). Similar results were also obtained with methoxsalen and tranylcypromine in human liver microsomes. R-(+)-Tranylcypromine, (±)-tranylcypromine, and S-(-)-tranylcypromine competitively inhibited CYP2A6-mediated metabolism of nicotine with apparent Ki values of 0.05, 0.08, and 2.0 µM, respectively. Tranylcypromine [particularly R-(+) isomer], tryptamine, and methoxsalen are specific and relatively selective for CYP2A6 and may be useful in vivo to decrease smoking by inhibiting nicotine metabolism with a low risk of metabolic drug interactions.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Ther Adv Respir DisHome page
L. Carrozzi, F. Pistelli, and G. Viegi
Review: Pharmacotherapy for smoking cessation
Therapeutic Advances in Respiratory Disease, October 1, 2008; 2(5): 301 - 317.
[Abstract] [PDF]

Home page
 Drug Metab. Dispos.Home page
D. S. Diaz, Michael. P. Kozar, K. S. Smith, C. O. Asher, J. C. Sousa, G. A. Schiehser, David. P. Jacobus, Wilbur. K. Milhous, Donald. R. Skillman, and Todd. W. Shearer
Role of Specific Cytochrome P450 Isoforms in the Conversion of Phenoxypropoxybiguanide Analogs in Human Liver Microsomes to Potent Antimalarial Dihydrotriazines
Drug Metab. Dispos., February 1, 2008; 36(2): 380 - 385.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
X. Zhang, J. D'Agostino, H. Wu, Q.-Y. Zhang, L. von Weymarn, S. E. Murphy, and X. Ding
CYP2A13: Variable Expression and Role in Human Lung Microsomal Metabolic Activation of the Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone
J. Pharmacol. Exp. Ther., November 1, 2007; 323(2): 570 - 578.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
E. Higashi, M. Nakajima, M. Katoh, S. Tokudome, and T. Yokoi
Inhibitory Effects of Neurotransmitters and Steroids on Human CYP2A6
Drug Metab. Dispos., April 1, 2007; 35(4): 508 - 514.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. I. Damaj, E. C. K. Siu, E. M. Sellers, R. F. Tyndale, and B. R. Martin
Inhibition of Nicotine Metabolism by Methoxysalen: Pharmacokinetic and Pharmacological Studies in Mice
J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 250 - 257.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
S. Agatsuma, M. Lee, H. Zhu, K. Chen, J. C. Shih, I. Seif, and N. Hiroi
Monoamine oxidase A knockout mice exhibit impaired nicotine preference but normal responses to novel stimuli
Hum. Mol. Genet., September 15, 2006; 15(18): 2721 - 2731.
[Abstract] [Full Text] [PDF]

Home page
 J PsychopharmacolHome page
A. M. Lee and R. F. Tyndale
Drugs and genotypes: how pharmacogenetic information could improve smoking cessation treatment
J Psychopharmacol, July 1, 2006; 20(4_suppl): 7 - 14.
[Abstract] [PDF]

Home page
 J Clin PharmacolHome page
M. Rheeders, M. Bouwer, and T. C. Goosen
Drug-drug interaction after single oral doses of the furanocoumarin methoxsalen and cyclosporine.
J. Clin. Pharmacol., July 1, 2006; 46(7): 768 - 775.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
A. Schmitz, A. Sankaranarayanan, P. Azam, K. Schmidt-Lassen, D. Homerick, W. Hansel, and H. Wulff
Design of PAP-1, a Selective Small Molecule Kv1.3 Blocker, for the Suppression of Effector Memory T Cells in Autoimmune Diseases
Mol. Pharmacol., November 1, 2005; 68(5): 1254 - 1270.
[Abstract] [Full Text] [PDF]

Home page
 PsychosomaticsHome page
N. B. Sandson, S. C. Armstrong, and K. L. Cozza
An Overview of Psychotropic Drug-Drug Interactions
Psychosomatics, October 1, 2005; 46(5): 464 - 494.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
K. Guillem, C. Vouillac, M. R. Azar, L. H. Parsons, G. F. Koob, M. Cador, and L. Stinus
Monoamine Oxidase Inhibition Dramatically Increases the Motivation to Self-Administer Nicotine in Rats
J. Neurosci., September 21, 2005; 25(38): 8593 - 8600.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
J. Hukkanen, P. Jacob III, and N. L. Benowitz
Metabolism and Disposition Kinetics of Nicotine
Pharmacol. Rev., March 1, 2005; 57(1): 79 - 115.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
L. B. von Weymarn, Q.-Y. Zhang, X. Ding, and P. F. Hollenberg
Effects of 8-methoxypsoralen on cytochrome P450 2A13
Carcinogenesis, March 1, 2005; 26(3): 621 - 629.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
W. Zhang, Y. Ramamoorthy, R. F. Tyndale, and E. M. Sellers
INTERACTION OF BUPRENORPHINE AND ITS METABOLITE NORBUPRENORPHINE WITH CYTOCHROMES P450 IN VITRO
Drug Metab. Dispos., June 1, 2003; 31(6): 768 - 772.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
K. A. Schoedel, E. M. Sellers, R. Palmour, and R. F. Tyndale
Down-Regulation of Hepatic Nicotine Metabolism and a CYP2A6-Like Enzyme in African Green Monkeys after Long-Term Nicotine Administration
Mol. Pharmacol., January 1, 2003; 63(1): 96 - 104.
[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 © 2001 by the American Society for Pharmacology and Experimental Therapeutics.