title: Age-Specific Regulation of Drug-Processing Genes in Mouse Liver by Ligands of Xenobiotic-Sensing Transcription Factors.
abstract: The xenobiotic-sensing transcription factors (xeno-sensors) AhR, CAR, and PXR upregulate the expression of many drug-processing genes (DPGs) in liver. Previous studies have unveiled profound changes in the basal expression of DPGs during development; however, knowledge on the ontogeny of the inducibility of DPGs in response to pharmacological activation of xeno-sensors is still limited. The goal of this study was to investigate the age-specific regulation of DPGs by prototypical xeno-sensor ligands: 2,3,7,8-tetrachlorodibenzodioxin (TCDD) for AhR; 1,4-bis [2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) for CAR; and pregnane-16α-carbonitrile (PCN) for PXR during mouse liver development. The basal mRNAs of most DPGs were low during neonatal age, but gradually increased to adult levels, whereas some DPGs (Cyp1a2, Cyp2b10, Cyp3a11, Gstm2, Gstm3, Papss2, and Oatp1a4) exhibited an adolescent-predominant expression pattern. The inducibility of DPGs was age-specific: 1) during neonatal age, the highest fold increase in the mRNA expression was observed for Cyp1a2, Sult5a1, and Ugt1a9 by TCDD; Cyp3a11 and Mrp2 by TCPOBOP; as well as Gstm2 and Gstm3 by PCN; 2) during adolescent age, the highest fold increase in the mRNA expression was observed for Ugt1a6 and Mrp4 by TCDD, Cyp2b10, Ugt2b34, and Ugt2b35 by TCPOBOP, as well as Gsta1, Gsta4, Sult1e1, Ugt1a1, Mrp3, and Mrp4 by PCN; 3) in adults, the highest fold increase in the mRNA expression was observed for Aldh1a1, Aldh1a7, and Ugt2b36 by TCPOBOP, as well as Papss2 and Oatp1a4 by PCN. In conclusion, the inducibility of hepatic DPGs following the pharmacological activation of xeno-sensors is age specific.
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington (C.Y.L., C.D.K., J.Y.C.); and Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas (H.J.R.).
authors.forename: Cindy Yanfei
authors.initials: CY
authors.lastname: Li
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington (C.Y.L., C.D.K., J.Y.C.); and Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas (H.J.R.).
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Renaud
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington (C.Y.L., C.D.K., J.Y.C.); and Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas (H.J.R.).
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington (C.Y.L., C.D.K., J.Y.C.); and Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas (H.J.R.) juliacui@uw.edu.
authors.forename: Julia Yue
authors.initials: JY
authors.lastname: Cui
mesh_terms: D000367:Age Factors; D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists* / Q000378:metabolism; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists* / Q000378:metabolism; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism
chemical_list: D000444:Aldehyde Dehydrogenase; D051792:Basic Helix-Loop-Helix Proteins; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D008024:Ligands; D027701:Organic Cation Transport Proteins; D000072317:Polychlorinated Dibenzodioxins; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile; D011725:Pyridines; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015238:Sulfotransferases; C484722:Ahr protein, mouse; C464433:Oatp2 protein, mouse; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene