Comparison of the ligand binding site of CYP2C8 with CYP26A1 and CYP26B1: a structural basis for the identification of new inhibitors of the retinoic acid hydroxylases

Abstract

The CYP26s are responsible for metabolizing retinoic acid and play an important role in maintaining homeostatic levels of retinoic acid. Given the ability of CYP2C8 to metabolize retinoic acid, we evaluated the potential for CYP2C8 inhibitors to also inhibit CYP26. In vitro assays were used to evaluate the inhibition potencies of CYP2C8 inhibitors against CYP26A1 and CYP26B1. Using tazarotenic acid as a substrate for CYP26, IC₅₀ values for 17 inhibitors of CYP2C8 were determined for CYP26A1 and CYP26B1, ranging from ∼20 nM to 100 μM, with a positive correlation observed between IC₅₀s for CYP2C8 and CYP26A1. An evaluation of IC₅₀’s versus in vivo C_max values suggests that inhibitors such as clotrimazole or fluconazole may interact with CYP26 at clinically relevant concentrations and may alter levels of retinoic acid. These findings provide insight into drug interactions resulting in elevated retinoic acid concentrations and expand upon the pharmacophore of CYP26 inhibition.

Keywords:

• CYP26
• CYP2C8
• homology model
• retinoic acid
• tazarotenic acid

Acknowledgements

The authors thank Dr. Nina Isoherranen (University of Washington) for her insightful critique of our manuscript and Dr. Alex Zelter (University of Washington) for the expression and characterization of the recombinantly expressed CYP26A1 and CYP26B1 enzymes used in this research.

Declaration of interest

Philippe Diaz is the co-founder and chief scientific officer of Dermaxon. The authors declare no additional competing financial interests. This research in this manuscript was funded by Amgen Inc. (Thousand Oaks, CA), l’Institut National de la Santé et de la Recherche Médicale (INSERM), 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.