Abstract

The long-term objective of this proposal is to identify interactions between xenobiotics and CYP26 enzymes that lead to altered all-trans retinoic acid (RA) concentrations in plasma and in different tissues. This is important because accurate control of RA concentrations is critical for reproduction, fetal and placental development, maintenance of epithelia, regulation of immunity and apoptosis and cancer prevention and treatment. Compounds that alter RA elimination by inhibiting or inducing the enzymes responsible for RA metabolism have the potential to cause multiple detrimental effects on individuals'health. The central hypothesis of this grant proposal is that CYP26 enzymes regulate circulating RA concentrations and control the clearance of RA in vivo. This hypothesis will be tested by the three specific aims designed to provide a comprehensive characterization of the role of CYP26A1 and CYP26B1 in regulating RA homeostasis. The first specific aim of this proposal is to demonstrate that CYP26A1 and CYP26B1 are the major RA hydroxylases in adult human tissues. The second specific aim is to identify xenobiotic and endogenous ligands of CYP26A1 and CYP26B1.
Aim 3 will test the effect of selected xenobiotics on CYP26A1 and CYP26B1 expression and RA metabolism in human tissues and cell lines. The results of these aims will provide important basic understanding of the function and substrate specificity of CYP26A1 and CYP26B1, two understudied and poorly characterized P450 enzymes. Tight regulation of cellular retinoic acid concentrations is essential for normal reproduction, immune competence, maintenance of healthy epithelia and bone health and for regulation of apoptosis and cell division. As such, alteration of the processes that control cellular retinoic acid metabolism can cause multiple detrimental effects on an individual's health. This proposal aims at characterizing interactions between xenobiotics and retinoic acid metabolizing CYP26 enzymes that alter retinoic acid metabolism and clearance and can lead to adverse effects.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM081569-04
Application #
8024507
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
2008-03-10
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
4
Fiscal Year
2011
Total Cost
$280,885
Indirect Cost

  Institution

Name
University of Washington
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Arnold, Samuel L; Stevison, Faith; Isoherranen, Nina (2016) Impact of Sample Matrix on Accuracy of Peptide Quantification: Assessment of Calibrator and Internal Standard Selection and Method Validation. Anal Chem 88:746-53
Brindisi, Margherita; Maramai, Samuele; Gemma, Sandra et al. (2016) Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain. J Med Chem 59:2612-32
Diaz, Philippe; Huang, Weize; Keyari, Charles M et al. (2016) Development and Characterization of Novel and Selective Inhibitors of Cytochrome P450 CYP26A1, the Human Liver Retinoic Acid Hydroxylase. J Med Chem 59:2579-95
Tripathy, Sasmita; Chapman, John D; Han, Chang Y et al. (2016) All-Trans-Retinoic Acid Enhances Mitochondrial Function in Models of Human Liver. Mol Pharmacol 89:560-74
Foti, Robert S; Isoherranen, Nina; Zelter, Alex et al. (2016) Identification of Tazarotenic Acid as the First Xenobiotic Substrate of Human Retinoic Acid Hydroxylase CYP26A1 and CYP26B1. J Pharmacol Exp Ther 357:281-92
Nelson, Cara H; Peng, Chi-Chi; Lutz, Justin D et al. (2016) Direct protein-protein interactions and substrate channeling between cellular retinoic acid binding proteins and CYP26B1. FEBS Lett 590:2527-35
Stevison, Faith; Jing, Jing; Tripathy, Sasmita et al. (2015) Role of Retinoic Acid-Metabolizing Cytochrome P450s, CYP26, in Inflammation and Cancer. Adv Pharmacol 74:373-412
Arnold, Samuel L; Kent, Travis; Hogarth, Cathryn A et al. (2015) Importance of ALDH1A enzymes in determining human testicular retinoic acid concentrations. J Lipid Res 56:342-57
Arnold, Samuel L M; Kent, Travis; Hogarth, Cathryn A et al. (2015) Pharmacological inhibition of ALDH1A in mice decreases all-trans retinoic acid concentrations in a tissue specific manner. Biochem Pharmacol 95:177-92
Topletz, Ariel R; Tripathy, Sasmita; Foti, Robert S et al. (2015) Induction of CYP26A1 by metabolites of retinoic acid: evidence that CYP26A1 is an important enzyme in the elimination of active retinoids. Mol Pharmacol 87:430-41

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