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  - 
TY  - JOUR
A1  - Luisier, Raphaëlle
A1  - Lempiäinen, Harri
A1  - Scherbichler, Nina
A1  - Braeuning, Albert
A1  - Geissler, Miriam
A1  - Dubost, Valerie
A1  - Müller, Arne
A1  - Scheer, Nico
A1  - Chibout, Salah-Dine
A1  - Hara, Hisanori
A1  - Picard, Frank
A1  - Theil, Diethilde
A1  - Couttet, Philippe
A1  - Vitobello, Antonio
A1  - Grenet, Olivier
A1  - Grasl-Kraupp, Bettina
A1  - Ellinger-Ziegelbauer, Heidrung
A1  - Thomson, John P.
A1  - Meehan, Richard R.
A1  - Elcombe, Clifford R.
A1  - Henderson, Colin J.
A1  - Wolf, C. Roland
A1  - Schwarz, Michael
A1  - Moulin, Pierre
A1  - Terranova, Remi
A1  - Moggs, Jonathan G.
T1  - Phenobarbital Induces Cell Cycle Transcriptional Responses in Mouse Liver Humanized for Constitutive Androstane and Pregnane X Receptors
JF  - Toxicological Sciences
N2  - The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcinogenesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CARᴷᴼ-PXRᴷᴼ), double humanized CAR and PXR (CARʰ-PXRʰ), and wild-type C57BL/6 mice. Wild-type and CARʰ-PXRʰ mouse livers exhibited temporally and quantitatively similar transcriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1) and the proliferation-related nuclear antigen Mki67 were observed with peak expression occurring between 1 and 7 days PB exposure. All these transcriptional responses were absent in CARᴷᴼ-PXRᴷᴼ mouse livers and largely reversible in wild-type and CARʰ-PXRʰ mouse livers following 91 days of PB exposure and a subsequent 4-week recovery period. Furthermore, PB-mediated upregulation of the noncoding RNA Meg3, which has recently been associated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CARʰ-PXRʰ mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB.
Y1  - 2014
U6  - http://dx.doi.org/https://doi.org/10.1093/toxsci/kfu038
SN  - 1094-2025
VL  - 139
IS  - 2
SP  - 501
EP  - 511
PB  - Oxford University Press
CY  - Oxford
ER  -