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Research ArticleArticle

STRUCTURAL AND ENZYMATIC PARAMETERS THAT DETERMINE ALKYL DEHYDROGENATION/HYDROXYLATION OF CAPSAICINOIDS BY CYTOCHROME P450 ENZYMES

Christopher A. Reilly and Garold S. Yost
Drug Metabolism and Disposition April 2005, 33 (4) 530-536; DOI: https://doi.org/10.1124/dmd.104.001214
Christopher A. Reilly
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Garold S. Yost
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Abstract

Previous studies on the metabolism of capsaicinoids, natural products isolated from chili peppers, demonstrated the production of unique macrocyclic, alkyl dehydrogenated, ω-, and ω-1-hydroxylated products. This study investigated the structural and enzymatic parameters that direct selective alkyl dehydrogenation and hydroxylation of capsaicinoids, using a variety of structurally related capsaicinoid analogs and cytochrome P450 (P450) enzymes. CYP2C9 preferentially catalyzed alkyl dehydrogenation, whereas CYP2E1 and 3A4 catalyzed ω- and ω-1-hydroxylation, respectively. Analysis of incubations containing various P450s and structural variants of capsaicin by liquid chromatography-tandem mass spectrometry demonstrated similarities in the rate of capsaicinoid metabolism, but marked differences in the metabolite profiles. Production of macrocyclic and ω-1-hydroxylated metabolites from the various capsaicinoids was dependent on the structure of the alkyl terminus and P450 enzyme. A tertiary carbon at the ω-1 position, coupled to an adjacent unsaturated bond at the ω-2,3 position, enhanced the formation of the macrocyclic and dehydrogenated metabolites and were requisite structural features for ω-1-hydroxylated product formation. Conversely, substrates lacking these structural features were efficiently oxidized to the ω-hydroxylated metabolite. These data were consistent with our hypothesis that metabolism of the alkyl portion of capsaicinoids was governed, in part, by the stability and propensity to form an intermediate radical and a carbocation, and a direct interaction between the alkyl terminus and the heme of many P450 enzymes. These results provided valuable insights into potential mechanisms by which P450s metabolize capsaicinoids and highlight critical chemical features that may also govern the metabolism of structurally related compounds including fatty acids, monoter-penes, and isoprenoids.

Footnotes

  • This work was supported by grants from the National Heart, Lung, and Blood Institute (HL069813 and HL13645) and a contract from the National Institute of Standards and Technology (Department of Commerce Contract 60NAN-BOD0006).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.104.001214.

  • ABBREVIATIONS: TRPV1, capsaicin receptor transient receptor potential V1; NADPH, reduced nicotinamide adenine dinucleotide phosphate; P450, cytochrome P450; HPLC, high-performance liquid chromatography; LC/MS/MS, liquid chromatography-tandem mass spectrometry; amu, atomic mass unit(s).

    • Received June 29, 2004.
    • Accepted January 5, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (4)
Drug Metabolism and Disposition
Vol. 33, Issue 4
1 Apr 2005
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Research ArticleArticle

STRUCTURAL AND ENZYMATIC PARAMETERS THAT DETERMINE ALKYL DEHYDROGENATION/HYDROXYLATION OF CAPSAICINOIDS BY CYTOCHROME P450 ENZYMES

Christopher A. Reilly and Garold S. Yost
Drug Metabolism and Disposition April 1, 2005, 33 (4) 530-536; DOI: https://doi.org/10.1124/dmd.104.001214

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Research ArticleArticle

STRUCTURAL AND ENZYMATIC PARAMETERS THAT DETERMINE ALKYL DEHYDROGENATION/HYDROXYLATION OF CAPSAICINOIDS BY CYTOCHROME P450 ENZYMES

Christopher A. Reilly and Garold S. Yost
Drug Metabolism and Disposition April 1, 2005, 33 (4) 530-536; DOI: https://doi.org/10.1124/dmd.104.001214
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