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Research ArticleMetabolism, Transport, and Pharmacogenomics

Identification of Tazarotenic Acid as the First Xenobiotic Substrate of Human Retinoic Acid Hydroxylase CYP26A1 and CYP26B1

Robert S Foti, Nina Isoherranen, Alex Zelter, Leslie J Dickmann, Brian R Buttrick, Philippe Diaz and Dominique Douguet
Journal of Pharmacology and Experimental Therapeutics March 2, 2016, jpet.116.232637; DOI: https://doi.org/10.1124/jpet.116.232637
Robert S Foti
1 Amgen;
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Nina Isoherranen
2 University of Washington;
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Alex Zelter
2 University of Washington;
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Leslie J Dickmann
3 Genentech;
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Brian R Buttrick
2 University of Washington;
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Philippe Diaz
4 University of Montana;
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Dominique Douguet
5 University of Nice - Sophia Antipolis
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Abstract

Cytochrome P450 26A1 and 26B1 are heme-containing enzymes responsible for metabolizing all-trans retinoic acid (at-RA). No crystal structures have been solved and therefore homology models that provide structural information are extremely valuable for the development of inhibitors of CYP26. The objectives of this study were to utilize homology models of CYP26A1 and CYP26B1 to characterize substrate binding characteristics, compare structural aspects of their active sites and to support the role of CYP26 in the metabolism of xenobiotics. Each model was verified by docking at-RA in the active site and comparing the results to known metabolic profiles of at-RA. The models were then used to predict the metabolic sites of tazarotenic acid and the results verified by in vitro metabolite identification experiments. The CYP26A1 and CYP26B1 homology models predicted that the benzothiopyranyl moiety of tazarotenic acid would be oriented towards the heme of each enzyme and suggested that tazarotenic acid would be a substrate of CYP26A1 and CYP26B1. Metabolite identification experiments indicated that CYP26A1 and CYP26B1 oxidatively metabolized tazarotenic acid on the predicted moiety, with in vitro rates of metabolite formation by CYP26A1 and CYP26B1 being the highest across a panel of enzymes. Molecular analysis of the active sites estimated the active site volumes of CYP26A1 and CYP26B1 to be 918 Å3 and 977 Å3, respectively. Overall, the homology models presented herein describe the enzyme characteristics leading to the metabolism of tazarotenic acid by CYP26A1 and CYP26B1 and support a potential role for the CYP26 enzymes in the metabolism of xenobiotics.

  • 9-cis-retinoic acid
  • computational models
  • cytochrome P450 regulation
  • retinoid metabolism
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 377 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 377, Issue 2
1 May 2021
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Identification of Tazarotenic Acid as the First Xenobiotic Substrate of Human Retinoic Acid Hydroxylase CYP26A1 and CYP26B1

Robert S Foti, Nina Isoherranen, Alex Zelter, Leslie J Dickmann, Brian R Buttrick, Philippe Diaz and Dominique Douguet
Journal of Pharmacology and Experimental Therapeutics March 2, 2016, jpet.116.232637; DOI: https://doi.org/10.1124/jpet.116.232637

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Identification of Tazarotenic Acid as the First Xenobiotic Substrate of Human Retinoic Acid Hydroxylase CYP26A1 and CYP26B1

Robert S Foti, Nina Isoherranen, Alex Zelter, Leslie J Dickmann, Brian R Buttrick, Philippe Diaz and Dominique Douguet
Journal of Pharmacology and Experimental Therapeutics March 2, 2016, jpet.116.232637; DOI: https://doi.org/10.1124/jpet.116.232637
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