title: Enhanced thyroid hormone breakdown in hepatocytes by mutual induction of the constitutive androstane receptor (CAR, NR1I3) and arylhydrocarbon receptor by benzo[a]pyrene and phenobarbital.
abstract: Xenobiotics may interfere with the hypothalamic-pituitary-thyroid endocrine axis by inducing enzymes that inactivate thyroid hormones and thereby reduce the metabolic rate. This induction results from an activation of xeno-sensing nuclear receptors. The current study shows that benzo[a]pyrene, a frequent contaminant of processed food and activator of the arylhydrocarbon receptor (AhR) activated the promoter and induced the transcription of the nuclear receptor constitutive androstane receptor (CAR, NR1I3) in rat hepatocytes. Likewise, phenobarbital induced the AhR transcription. This mutual induction of the nuclear receptors enhanced the phenobarbital-dependent induction of the prototypic CAR target gene Cyp2b1 as well as the AhR-dependent induction of UDP-glucuronosyltransferases. In both cases, the induction by the combination of both xenobiotics was more than the sum of the induction by either substance alone. By inducing the AhR, phenobarbital enhanced the benzo[a]pyrene-dependent reduction of thyroid hormone half-life and the benzo[a]pyrene-dependent increase in the rate of thyroid hormone glucuronide formation in hepatocyte cultures. CAR ligands might thus augment the endocrine disrupting potential of AhR activators by an induction of the AhR.
authors.affiliation: University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Schraplau
authors.affiliation: University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Schewe
authors.affiliation: University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Neuschäfer-Rube
authors.affiliation: University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ringel
authors.affiliation: Department of Nutritional Toxicology, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Neuber
authors.affiliation: Department of Nutritional Toxicology, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
authors.affiliation: University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. Electronic address: gpuesche@uni-potsdam.de.
authors.forename: Gerhard P
authors.initials: GP
authors.lastname: Püschel
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis; D065693:Cytochrome P-450 Enzyme Inducers / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D052244:Endocrine Disruptors / Q000633:toxicity*; D004790:Enzyme Induction; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D006207:Half-Life; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010634:Phenobarbital / Q000633:toxicity*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D059748:Proteolysis; D051381:Rats; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013963:Thyroid Hormones / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001564:Benzo(a)pyrene; D000090702:Constitutive Androstane Receptor; D019362:Cytochrome P-450 CYP2B1; D065693:Cytochrome P-450 Enzyme Inducers; D052244:Endocrine Disruptors; D020719:Glucuronides; D014453:Glucuronosyltransferase; D010634:Phenobarbital; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D013963:Thyroid Hormones; C000595703:Ahr protein, rat; C000716329:Nr1i3 protein, rat
keywords: Aryl-hydrocarbon receptor; Cyp2b1; Endocrine disruption; Thyroid hormone; UDP-glucuronosyltransferase; Xenobesity