TY  - JOUR
A1  - Lempiäinen, Harri
A1  - Couttet, Philippe
A1  - Bolognani, Federico
A1  - Müller, Arne
A1  - Dubost, Valérie
A1  - Luisier, Raphaëlle
A1  - Rio-Espinola, Alberto del
A1  - Vitry, Veronique
A1  - Unterberger, Elif B.
A1  - Thomson, John P.
A1  - Treindl, Fridolin
A1  - Metzger, Ute
A1  - Wrzodek, Clemens
A1  - Hahne, Florian
A1  - Zollinger, Tulipan
A1  - Brasa, Sarah
A1  - Kalteis, Magdalena
A1  - Marcellin, Magali
A1  - Giudicelli, Fanny
A1  - Braeuning, Albert
A1  - Morawiec, Laurent
A1  - Zamurovic, Natasa
A1  - Längle, Ulrich
A1  - Scheer, Nico
A1  - Schübeler, Dirk
A1  - Goodman, Jay
A1  - Chibout, Salah-Dine
A1  - Marlowe, Jennifer
A1  - Theil, Dietlinde
A1  - Heard, David J.
A1  - Grenet, Olivier
A1  - Zell, Andreas
A1  - Templin, Markus F.
A1  - Meehan, Richard R.
A1  - Wolf, Roland C.
A1  - Elcombe, Clifford R.
A1  - Schwarz, Michael
A1  - Moulin, Pierre
A1  - Terranova, Rémi
A1  - Moggs, Jonathan G.
T1  - Identification of Dlk1-Dio3 imprinted gene cluster non-coding RNAs as novel candidate biomarkers for liver tumor promotion
JF  - Toxicological Sciences
N2  - The molecular events during nongenotoxic carcinogenesis and their temporal order are poorly understood but thought to include long-lasting perturbations of gene expression. Here, we have investigated the temporal sequence of molecular and pathological perturbations at early stages of phenobarbital (PB) mediated liver tumor promotion in vivo. Molecular profiling (mRNA, microRNA [miRNA], DNA methylation, and proteins) of mouse liver during 13 weeks of PB treatment revealed progressive increases in hepatic expression of long noncoding RNAs and miRNAs originating from the Dlk1-Dio3 imprinted gene cluster, a locus that has recently been associated with stem cell pluripotency in mice and various neoplasms in humans. PB induction of the Dlk1-Dio3 cluster noncoding RNA (ncRNA) Meg3 was localized to glutamine synthetase-positive hypertrophic perivenous hepatocytes, sug- gesting a role for β-catenin signaling in the dysregulation of Dlk1-Dio3 ncRNAs. The carcinogenic relevance of Dlk1-Dio3 locus ncRNA induction was further supported by in vivo genetic dependence on constitutive androstane receptor and β-catenin pathways. Our data identify Dlk1-Dio3 ncRNAs as novel candidate early biomarkers for mouse liver tumor promotion and provide new opportunities for assessing the carcinogenic potential of novel compounds.
Y1  - 2012
U6  - http://dx.doi.org/10.1093/toxsci/kfs303
SN  - 1094-2025
VL  - 131
IS  - 2
SP  - 375
EP  - 386
PB  - Oxford University Press
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Scheer, Nico
A1  - Mclaughlin, Lesley A.
A1  - Rode, Anja
A1  - MacLeod, Alastair Kenneth
A1  - Henderson, Colin J.
A1  - Wolf, Roland C.
T1  - Deletion of thirty murine cytochrome P450 genes results in viable mice with compromised drug metabolism
JF  - Drug Metabolism and Disposition
N2  - In humans, 75% of all drugs are metabolized by the cytochrome P450-dependent monooxygenase system. Enzymes encoded by the CYP2C, CYP2D, and CYP3A gene clusters account for ∼80% of this activity. There are profound species differences in the multiplicity of cytochrome P450 enzymes, and the use of mouse models to predict pathways of drug metabolism is further complicated by overlapping substrate specificity between enzymes from different gene families. To establish the role of the hepatic and extrahepatic P450 system in drug and foreign chemical disposition, drug efficacy, and toxicity, we created a unique mouse model in which 30 cytochrome P450 genes from the Cyp2c, Cyp2d, and Cyp3a gene clusters have been deleted. Remarkably, despite a wide range of putative important endogenous functions, Cyp2c/2d/3a KO mice were viable and fertile, demonstrating that these genes have evolved primarily as detoxification enzymes. Although there was no overt phenotype, detailed examination showed Cyp2c/2d/3a KO mice had a smaller body size (15%) and larger livers (20%). Changes in hepatic morphology and a decreased blood glucose (30%) were also noted. A five-drug cocktail of cytochrome P450 isozyme probe substrates were used to evaluate changes in drug pharmacokinetics; marked changes were observed in either the pharmacokinetics or metabolites formed from Cyp2c, Cyp2d, and Cyp3a substrates, whereas the metabolism of the Cyp1a substrate caffeine was unchanged. Thus, Cyp2c/2d/3a KO mice provide a powerful model to study the in vivo role of the P450 system in drug metabolism and efficacy, as well as in chemical toxicity.
Y1  - 2014
U6  - http://dx.doi.org/10.1124/dmd.114.057885
SN  - 1521-009X
VL  - 42
IS  - 6
SP  - 1022
EP  - 1030
PB  - ASPET
CY  - Bethesda, Md.
ER  -