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.
|Lee, Choon-myung; Lee, Bang-sub; Arnold, Samuel L et al. (2014) Nitric oxide and interleukin-1* stimulate the proteasome-independent degradation of the retinoic acid hydroxylase CYP2C22 in primary rat hepatocytes. J Pharmacol Exp Ther 348:141-52|
|Nya-Ngatchou, J J; Arnold, S L M; Walsh, T J et al. (2013) Intratesticular 13-cis retinoic acid is lower in men with abnormal semen analyses: a pilot study. Andrology 1:325-31|
|Topletz, Ariel R; Le, Huong N; Lee, Nora et al. (2013) Hepatic Cyp2d and Cyp26a1 mRNAs and activities are increased during mouse pregnancy. Drug Metab Dispos 41:312-9|
|Nelson, Cara H; Buttrick, Brian R; Isoherranen, Nina (2013) Therapeutic potential of the inhibition of the retinoic acid hydroxylases CYP26A1 and CYP26B1 by xenobiotics. Curr Top Med Chem 13:1402-28|
|Wen, Jiadi; Lopes, Fatima; Soares, Gabriela et al. (2013) Phenotypic and functional consequences of haploinsufficiency of genes from exocyst and retinoic acid pathway due to a recurrent microdeletion of 2p13.2. Orphanet J Rare Dis 8:100|
|Topletz, Ariel R; Thatcher, Jayne E; Zelter, Alex et al. (2012) Comparison of the function and expression of CYP26A1 and CYP26B1, the two retinoic acid hydroxylases. Biochem Pharmacol 83:149-63|
|Arnold, Samuel L M; Amory, John K; Walsh, Thomas J et al. (2012) A sensitive and specific method for measurement of multiple retinoids in human serum with UHPLC-MS/MS. J Lipid Res 53:587-98|
|Amory, John K; Muller, Charles H; Shimshoni, Jakob A et al. (2011) Suppression of spermatogenesis by bisdichloroacetyldiamines is mediated by inhibition of testicular retinoic acid biosynthesis. J Androl 32:111-9|
|Thatcher, Jayne E; Buttrick, Brian; Shaffer, Scott A et al. (2011) Substrate specificity and ligand interactions of CYP26A1, the human liver retinoic acid hydroxylase. Mol Pharmacol 80:228-39|
|Thatcher, Jayne E; Zelter, Alex; Isoherranen, Nina (2010) The relative importance of CYP26A1 in hepatic clearance of all-trans retinoic acid. Biochem Pharmacol 80:903-12|
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