title: Novel roles for AhR and ARNT in the regulation of alcohol dehydrogenases in human hepatic cells.
abstract: The mechanisms by which pollutants participate in the development of diverse pathologies are not completely understood. The pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activates the AhR (aryl hydrocarbon receptor) signaling pathway. We previously showed that TCDD (25 nM, 30 h) decreased the expression of several alcohol metabolism enzymes (cytochrome P450 2E1, alcohol dehydrogenases ADH1, 4 and 6) in differentiated human hepatic cells (HepaRG). Here, we show that, as rapidly as 8 h after treatment (25 nM TCDD) ADH expression decreased 40 % (p < 0.05). ADH1 and 4 protein levels decreased 40 and 27 %, respectively (p < 0.05), after 72 h (25 nM TCDD). The protein half-lives were not modified by TCDD which suggests transcriptional regulation of expression. The AhR antagonist CH-223191 or AhR siRNA reduced the inhibitory effect of 25 nM TCDD on ADH1A, 4 and 6 expression 50-100 % (p < 0.05). The genomic pathway (via the AhR/ARNT complex) and not the non-genomic pathway involving c-SRC mediated these effects. Other AhR ligands (3-methylcholanthrene and PCB 126) decreased ADH1B, 4 and 6 mRNAs by more than 78 and 55 %, respectively (p < 0.01). TCDD also regulated the expression of ADH4 in the HepG2 human hepatic cell line, in primary human hepatocytes and in C57BL/6J mouse liver. In conclusion, activation of the AhR/ARNT signaling pathway by AhR ligands represents a novel mechanism for regulating the expression of ADHs. These effects may be implicated in the toxicity of AhR ligands as well as in the alteration of ethanol or retinol metabolism and may be associated further with higher risk of liver diseases or/and alcohol abuse disorders.
authors.affiliation: INSERM, UMR-S 1124, Toxicologie Pharmacologie et Signalisation Cellulaire, 45 rue des Saints Pères, F-75006, Paris, France.|ComUE Sorbonne Paris Cité, Université Paris Descartes, CICB-Paris, 45 rue des Saints Pères, F-75006, Paris, France.
authors.forename: Eléonore A
authors.initials: EA
authors.lastname: Attignon
authors.affiliation: INSERM, UMR-S 1124, Toxicologie Pharmacologie et Signalisation Cellulaire, 45 rue des Saints Pères, F-75006, Paris, France.|ComUE Sorbonne Paris Cité, Université Paris Descartes, CICB-Paris, 45 rue des Saints Pères, F-75006, Paris, France.
authors.forename: Alix F
authors.initials: AF
authors.lastname: Leblanc
authors.affiliation: INSERM, UMR-S 1124, Toxicologie Pharmacologie et Signalisation Cellulaire, 45 rue des Saints Pères, F-75006, Paris, France.|ComUE Sorbonne Paris Cité, Université Paris Descartes, CICB-Paris, 45 rue des Saints Pères, F-75006, Paris, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Le-Grand
authors.affiliation: INSERM, UMR-S 1124, Toxicologie Pharmacologie et Signalisation Cellulaire, 45 rue des Saints Pères, F-75006, Paris, France.|ComUE Sorbonne Paris Cité, Université Paris Descartes, CICB-Paris, 45 rue des Saints Pères, F-75006, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Duval
authors.affiliation: INSERM, UMR-S 1124, Toxicologie Pharmacologie et Signalisation Cellulaire, 45 rue des Saints Pères, F-75006, Paris, France.|ComUE Sorbonne Paris Cité, Université Paris Descartes, CICB-Paris, 45 rue des Saints Pères, F-75006, Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Aggerbeck
authors.affiliation: INSERM, UMR-S 1124, Toxicologie Pharmacologie et Signalisation Cellulaire, 45 rue des Saints Pères, F-75006, Paris, France.|ComUE Sorbonne Paris Cité, Université Paris Descartes, CICB-Paris, 45 rue des Saints Pères, F-75006, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Rouach
authors.affiliation: INSERM, UMR-S 1124, Toxicologie Pharmacologie et Signalisation Cellulaire, 45 rue des Saints Pères, F-75006, Paris, France. etienne.blanc@parisdescartes.fr.|ComUE Sorbonne Paris Cité, Université Paris Descartes, CICB-Paris, 45 rue des Saints Pères, F-75006, Paris, France. etienne.blanc@parisdescartes.fr.
authors.forename: Etienne B
authors.initials: EB
authors.lastname: Blanc
mesh_terms: D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002274:Carcinogens, Environmental / Q000633:toxicity; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008297:Male; D008748:Methylcholanthrene / Q000633:toxicity; D008810:Mice, Inbred C57BL; D010575:Pesticides / Q000633:toxicity; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D034622:RNA Interference; D011897:Random Allocation; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000426:Alcohol Dehydrogenase; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D002274:Carcinogens, Environmental; D007527:Isoenzymes; D008024:Ligands; D008748:Methylcholanthrene; D010575:Pesticides; D011078:Polychlorinated Biphenyls; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human; C497396:ARNT protein, human; C489332:ADH1B protein, human; C023035:3,4,5,3',4'-pentachlorobiphenyl
keywords: ADH; Dioxin; HepaRG; Persistant organic pollutant