title: Epigenetic determinants of CYP1A1 induction by the aryl hydrocarbon receptor agonist 3,3',4,4',5-pentachlorobiphenyl (PCB 126).
abstract: Many enzymes involved in xenobiotic metabolism, including cytochrome P450 (CYP) 1A1, are regulated by the aryl hydrocarbon receptor (AhR). 3,3',4,4',5-Penta chlorobiphenyl (PCB 126) is a potent ligand for AhR and can thus induce the expression of CYP1A1. Interestingly, we observed that human carcinoma cell lines derived from different types of epithelial cells displayed divergent degrees of CYP1A1 induction after exposure to PCB 126. Since epigenetic mechanisms are known to be involved in cell type-specific gene expression, we sought to assess the epigenetic determinants of CYP1A1 induction in these carcinoma cell lines. In contrast to HepG2 hepatocarcinoma cells, HeLa cervical carcinoma cells showed significantly lower levels of CYP1A1 mRNA expression following PCB 126 exposure. Our results show that the two cell lines maintained differences in the chromatin architecture along the CYP1A1 promoter region. Furthermore, treatment with the epigenetic modifiers, trichostatin A (TSA) and 5-aza-2'-deoxycytidine (5-Aza-dC), significantly increased the expression of CYP1A1 after PCB 126 treatment in HeLa cells. However, we did not observe apparent differences in methylation levels or specific location of CpG DNA methylation between the two cell lines in the analyzed CYP1A1 promoter region. Taken together, our findings suggest that the differences in CYP1A1 expression between HepG2 and HeLa cells are due to differences in the chromatin architecture of the CYP1A1 promoter and thus establish a role of epigenetic regulation in cell-specific CYP1A1 expression.
authors.affiliation: Interdisciplinary Graduate Program in Human Toxicology, the University of Iowa, Iowa City, IA 52242, USA. sabine-vorrink@uiowa.edu.
authors.forename: Sabine U
authors.initials: SU
authors.lastname: Vorrink
authors.affiliation: Department of Radiation Oncology, the University of Iowa, Iowa City, IA 52242, USA. danielle-hudachek@uiowa.edu.
authors.forename: Danielle R
authors.initials: DR
authors.lastname: Hudachek
authors.affiliation: Interdisciplinary Graduate Program in Human Toxicology, the University of Iowa, Iowa City, IA 52242, USA. frederick-domann@uiowa.edu.
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Domann
mesh_terms: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D018899:CpG Islands; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000378:metabolism
chemical_list: D002843:Chromatin; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; C012589:trichostatin A; D000077209:Decitabine; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1; D001374:Azacitidine; C023035:3,4,5,3',4'-pentachlorobiphenyl