title: Human cytochrome P450 1A1 is a novel target gene of liver X receptor α.
abstract: Cytochrome P450 (CYP) 1A1 is involved in the metabolic activation of polycyclic aromatic hydrocarbons (PAHs) and is induced by several compounds, including PAHs. The induction of CYP1A1 mediated by the aryl hydrocarbon receptor (AhR) has been well investigated; however, little has been reported on the mechanisms of CYP1A1 induction mediated by factors other than AhR. In this study, we investigated the involvement of liver X receptor alpha (LXRα) in the induction of CYP1A1. TO-901317, an LXRα ligand, induced CYP1A1 mRNA in a dose-dependent fashion. Luciferase reporter assays using HepG2 cells showed that TO-901317 was capable of activating the promoter of the CYP1A1 gene and that a direct repeat 4 (DR4) motif located in a region from -452 to -467 was required for the induction of CYP1A1 through LXRα. Specific binding of LXRα to this DR4 motif was confirmed by gel shift and chromatin immunoprecipitation assays. Co-treatment of HepG2 cells with TO-901317 and 2,3,7,8-tetrachlorodibenzo-p-dioxin, a typical AhR ligand, caused the synergistic induction of CYP1A1 mRNA. Thus, we propose that the expression of CYP1A1 is regulated by LXRα as well as by AhR, suggesting that exposure to both LXRα and AhR ligands can result in the alteration of individual susceptibility to environmental carcinogens metabolically activated by CYP1A1.
authors.affiliation: Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan. shibaharanrh@chugai-pharm.co.jp
authors.forename: Norihito
authors.initials: N
authors.lastname: Shibahara
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Masunaga
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Iwano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Kazuma
authors.initials: K
authors.lastname: Kiyotani
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kamataki
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D056945:Hep G2 Cells; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000502:physiology*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D019363:Cytochrome P-450 CYP1A1; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D013449:Sulfonamides; C000605213:NR1H3 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C569463:CYP1A1 protein, human