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Research ArticleArticle

In Vitro Inhibition of Cytochrome P450 Enzymes in Human Liver Microsomes by a Potent CYP2A6 inhibitor, trans-2-Phenylcyclopropylamine (Tranylcypromine), and Its Nonamine Analog, Cyclopropylbenzene

Päivi Taavitsainen, Risto Juvonen and Olavi Pelkonen
Drug Metabolism and Disposition March 2001, 29 (3) 217-222;
Päivi Taavitsainen
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Risto Juvonen
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Olavi Pelkonen
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Abstract

Currently, there are no selective, well characterized inhibitors for CYP2A6. Therefore, the effects oftrans-(±)-2-phenylcyclopropylamine (tranylcypromine), a potent CYP2A6 inhibitor, on human liver microsomal cytochromes P450 (CYP) were studied to elucidate its selectivity. The IC50value of tranylcypromine in coumarin 7-hydroxylation (CYP2A6 model activity) was 0.42 ± 0.07 μM and in chlorzoxazone 6-hydroxylation (CYP2E1 model activity) 3.0 ± 1.1 μM. The IC50 values for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 activities were >10 μM. Potency and selectivity of tranylcypromine were strongly dependent on the amine group, because its nonamine analog cyclopropylbenzene was much less potent inhibitor of CYP1A, CYP2A6, CYP2C19, and CYP2E1 activities and did not inhibit at all CYP2C9, CYP2D6, or CYP3A4 activities. In human liver microsomes tranylcypromine induced type II and cyclopropylbenzene type I difference spectrum. According to the double reciprocal analysis of these spectral responses both tranylcypromine and cyclopropylbenzene may have at least two P450-related binding sites in liver microsomes. TheKa values of tranylcypromine varied from 4.5 to 15.1 μM and −34.3 to 167 μM in microsomes derived from three different livers and of cyclopropylbenzene from −1.6 to 10.1 μM and −34.6 and 75.2 μM in the same liver microsomes. Based on these results, tranylcypromine seems an adequately selective CYP2A6 inhibitor for in vitro use.

Footnotes

  • Send reprint requests to: Päivi Taavitsainen, Department of Pharmacology and Toxicology, P.O. Box 5000, University of Oulu, FIN-90014 Finland. E-mail: paivi.taavitsainen{at}oulu.fi

  • This study was partially supported by the European Union Framework 4 Biomed2 project EUROCYP, by Orion Pharma, and by the Farmos Science and Research Foundation. This work was partially presented as an abstract in DMW/ISSX 2000 Congress, St. Andrews, Fife, Scotland, UK. Abstract appears in Drug Metab Rev (2000)32 (Suppl 1):111.

  • Abbreviations used are::
    CYP
    P450, cytochrome P450
    HPLC
    high-performance liquid chromatography
    rac
    racemic
    • Received August 14, 2000.
    • Accepted November 16, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (3)
Drug Metabolism and Disposition
Vol. 29, Issue 3
1 Mar 2001
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Research ArticleArticle

In Vitro Inhibition of Cytochrome P450 Enzymes in Human Liver Microsomes by a Potent CYP2A6 inhibitor, trans-2-Phenylcyclopropylamine (Tranylcypromine), and Its Nonamine Analog, Cyclopropylbenzene

Päivi Taavitsainen, Risto Juvonen and Olavi Pelkonen
Drug Metabolism and Disposition March 1, 2001, 29 (3) 217-222;

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Research ArticleArticle

In Vitro Inhibition of Cytochrome P450 Enzymes in Human Liver Microsomes by a Potent CYP2A6 inhibitor, trans-2-Phenylcyclopropylamine (Tranylcypromine), and Its Nonamine Analog, Cyclopropylbenzene

Päivi Taavitsainen, Risto Juvonen and Olavi Pelkonen
Drug Metabolism and Disposition March 1, 2001, 29 (3) 217-222;
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