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Research ArticleArticle

Characterization of Arachidonic Acid Metabolism by Rat Cytochrome P450 Enzymes: The Involvement of CYP1As

Ahmed A. El-Sherbeni and Ayman O.S. El-Kadi
Drug Metabolism and Disposition September 2014, 42 (9) 1498-1507; DOI: https://doi.org/10.1124/dmd.114.057836
Ahmed A. El-Sherbeni
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
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Ayman O.S. El-Kadi
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
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Abstract

Cytochrome P450 (P450) enzymes mediate arachidonic acid (AA) oxidation to several biologically active metabolites. Our aims in this study were to characterize AA metabolism by different recombinant rat P450 enzymes and to identify new targets for modulating P450-AA metabolism in vivo. A liquid chromatography-mass spectrometry method was developed and validated for the simultaneous measurements of AA and 15 of its P450 metabolites. CYP1A1, CYP1A2, CYP2B1, CYP2C6, and CYP2C11 were found to metabolize AA with high catalytic activity, and CYP2A1, CYP2C13, CYP2D1, CYP2E1, and CYP3A1 had lower activity. CYP1A1 and CYP1A2 produced ω-1→4 hydroxyeicosatetraenoic acids (HETEs) as 88.7 and 62.7%, respectively, of the total metabolites formed. CYP2C11 produced epoxyeicosatrienoic acids (EETs) as 61.3%, and CYP2C6 produced midchain HETEs and EETs as 48.3 and 29.4%, respectively, of the total metabolites formed. The formation of CYP1A1, CYP1A2, CYP2C6, and CYP2C11 major metabolites followed an atypical kinetic profile of substrate inhibition. CYP1As inhibition by α-naphthoflavone or anti-CYP1As antibodies significantly reduced ω-1→4 HETE formation in the lungs and liver, whereas CYP1As induction by 3-methylcholanthrene resulted in a significant increase in ω-1→4 HETEs formation in the heart, lungs, kidney, and livers by 370, 646, 532, and 848%, respectively. In conclusion, our results suggest that CYP1As and CYP2Cs are major players in the metabolism of AA. The significant contribution of CYP1As to AA metabolism and their strong inducibility suggest their possible use as targets for the prevention and treatment of several diseases.

Footnotes

    • Received February 26, 2014.
    • Accepted June 26, 2014.
  • This work was supported by a grant from the Canadian Institutes of Health Research (CIHR) [Grant MOP 106665]. A.A.E.-S. is the recipient of an Egyptian Government Scholarship.

  • dx.doi.org/10.1124/dmd.114.057836.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (9)
Drug Metabolism and Disposition
Vol. 42, Issue 9
1 Sep 2014
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Research ArticleArticle

Characterization of AA Metabolism by Rat P450

Ahmed A. El-Sherbeni and Ayman O.S. El-Kadi
Drug Metabolism and Disposition September 1, 2014, 42 (9) 1498-1507; DOI: https://doi.org/10.1124/dmd.114.057836

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Research ArticleArticle

Characterization of AA Metabolism by Rat P450

Ahmed A. El-Sherbeni and Ayman O.S. El-Kadi
Drug Metabolism and Disposition September 1, 2014, 42 (9) 1498-1507; DOI: https://doi.org/10.1124/dmd.114.057836
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