Cytochrome P450 (CYP) 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 cytochrome P450 family 26 (CYP26). The objectives of this study were to use homology models of CYP26A1 and CYP26B1 to characterize substrate binding characteristics, to 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 with 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 toward 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.
- Received February 2, 2016.
- Accepted February 26, 2016.
↵1 Current affiliation: Preclinical and Translational Pharmacokinetics, Genentech Inc., S. San Francisco, CA 94080
This research was supported in part by Amgen Inc. (Thousand Oaks, CA), by l’Institut National de la Santé et de la Recherche Médicale (INSERM), by the National Institutes of Health National Institute of General Medical Sciences [Grants R01-GM081569, R01-GM111772], by the National Institutes of Health National Institute of Aging [Grant R41AG046987], and by a RRIA award from the Michael J. Fox Foundation for Parkinson’s Research. Philippe Diaz is a cofounder and chief scientific officer of DermaXon. The authors declare no additional competing financial interests.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics