title: Mixed-ligand copper(II) complexes activate aryl hydrocarbon receptor AhR and induce CYP1A genes expression in human hepatocytes and human cell lines.
abstract: The effects of four copper(II) mixed-ligand complexes [Cu(qui1)(L)]NO3·H2O (1-3) and [Cu(qui2)(phen)]NO3 (4), where qui1=2-phenyl-3-hydroxy-4(1H)-quinolinone, Hqui2=2-(4-amino-3,5-dichlorophenyl)-N-propyl-3-hydroxy-4(1H)-quinolinone-7-carboxamide, L=1,10-phenanthroline (phen) (1), 5-methyl-1,10-phenanthroline (mphen) (2), bathophenanthroline (bphen) (3), on transcriptional activities of steroid receptors, nuclear receptors and xenoreceptors have been studied. The complexes (1-4) did not influence basal or ligand-inducible activities of glucocorticoid receptor, androgen receptor, thyroid receptor, pregnane X receptor and vitamin D receptor, as revealed by gene reporter assays. The complexes 1 and 2 dose-dependently induced luciferase activity in stable gene reporter AZ-AhR cell line, and this induction was reverted by resveratrol, indicating involvement of aryl hydrocarbon receptor (AhR) in the process. The complexes 1, 2 and 3 induced CYP1A1 mRNA in LS180 cells and CYP1A1/CYP1A2 in human hepatocytes through AhR. Electrophoretic mobility shift assay EMSA showed that the complexes 1 and 2 transformed AhR in its DNA-binding form. Collectively, we demonstrate that the complexes 1 and 2 activate AhR and induce AhR-dependent genes in human hepatocytes and cancer cell lines. In conclusion, the data presented here might be of toxicological importance, regarding the multiple roles of AhR in human physiology and pathophysiology.
authors.affiliation: Department of Cell Biology and Genetics, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27(,) CZ-783 71 Olomouc, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Kubešová
authors.affiliation: Department of Cell Biology and Genetics, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27(,) CZ-783 71 Olomouc, Czech Republic.
authors.forename: Aneta
authors.initials: A
authors.lastname: Dořičáková
authors.affiliation: Department of Inorganic Chemistry, Faculty of Science, Palacký University, 17.listopadu 12, CZ-771 46 Olomouc, Czech Republic.
authors.forename: Zdeněk
authors.initials: Z
authors.lastname: Trávníček
authors.affiliation: Department of Cell Biology and Genetics, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27(,) CZ-783 71 Olomouc, Czech Republic. Electronic address: moulin@email.cz.
authors.forename: Zdeněk
authors.initials: Z
authors.lastname: Dvořák
mesh_terms: D000328:Adult; D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D003300:Copper / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D008297:Male; D008875:Middle Aged; D009566:Nitrates / Q000633:toxicity*; D010618:Phenanthrolines / Q000633:toxicity*; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003300:Copper; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D008024:Ligands; D009566:Nitrates; D010618:Phenanthrolines; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human; C516433:copper(II) nitrate; C569463:CYP1A1 protein, human; C504573:CYP1A2 protein, human; C025205:1,10-phenanthroline
keywords: Copper(II) complexes; Cytochrome P450; Human hepatocytes; Nuclear receptors; Xenobiotics