title: CYP2S1 is negatively regulated by corticosteroids in human cell lines.
abstract: Cytochrome P450s are monooxygenase proteins involved in the metabolism of both exogenous and endogenous compounds. CYP2S1 can metabolize eicosanoids in the absence of both NADPH and NADPH cytochrome P450 reductase, and can also activate the anticancer agent 1 AQ4N [1,4-bis{[2-(dimethylamino-N-oxide)ethyl]amino}-5,8-dihydroxy anthracene-9,10-dione]. CYP2S1 is mainly expressed in extrahepatic tissues such as the trachea, lung, stomach, small intestine, spleen, skin, breast, kidney and placenta. Furthermore, increased expression of CYP2S1 occurs in several tumors of epithelial origin, making the characterization of CYP2S1 regulation relevant to the treatment of disease. We report that the synthetic glucocorticoid receptor ligand dexamethasone (DEX) represses CYP2S1 expression. The ED(50) is between 1 nM and 3 nM and maximal repression is reached by 48 h. Other corticosteroids are also effective at repressing CYP2S1. We show that repression by DEX is mediated by the glucocorticoid receptor and requires histone deacetylase activity.
authors.affiliation: Molecular Toxicology Interdepartmental Program, Department of Pathology and Laboratory Medicine, and the Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA.
authors.forename: Ilona G
authors.initials: IG
authors.lastname: Bebenek
authors.forename: Parrisa
authors.initials: P
authors.lastname: Solaimani
authors.forename: Peter
authors.initials: P
authors.lastname: Bui
authors.forename: Oliver
authors.initials: O
authors.lastname: Hankinson
mesh_terms: D000305:Adrenal Cortex Hormones / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003609:Dactinomycin / Q000494:pharmacology; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000187:drug effects
chemical_list: D000305:Adrenal Cortex Hormones; D065607:Cytochrome P-450 Enzyme Inhibitors; D006877:Hydroxamic Acids; D007527:Isoenzymes; D011500:Protein Synthesis Inhibitors; D011965:Receptors, Glucocorticoid; D003609:Dactinomycin; C012589:trichostatin A; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; C422564:CYP2S1 protein, human; D006655:Histone Deacetylases