TY  - JOUR
A1  - Scheer, Nico
A1  - Kapelyukh, Yury
A1  - Rode, Anja
A1  - Oswald, Stefan
A1  - Busch, Diana
A1  - Mclaughlin, Lesley A.
A1  - Lin, De
A1  - Henderson, Colin J.
A1  - Wolf, C. Roland
T1  - Defining Human Pathways of Drug Metabolism In Vivo through the Development of a Multiple Humanized Mouse Model
JF  - Drug Metabolism and Disposition
Y1  - 2015
U6  - http://dx.doi.org/10.1124/dmd.115.065656
SN  - 1521-009x
VL  - 43
IS  - 11
SP  - 1679
EP  - 1690
PB  - ASPET
CY  - Bethesda
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  - 
TY  - JOUR
A1  - Ross, Jillian
A1  - Plummer, Simon M.
A1  - Rode, Anja
A1  - Scheer, Nico
A1  - Bower, Conrad C.
A1  - Vogel, Ortwin
A1  - Henderson, Colin J.
A1  - Wolf, C. Roland
A1  - Elcombe, Clifford R.
T1  - Human constitutive androstane receptor (CAR) and pregnane X receptor (PXR) support the  hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogens phenobarbital and chlordane in vivo
JF  - Toxicological Sciences
N2  - Mouse nongenotoxic hepatocarcinogens phenobarbital (PB) and chlordane induce hepatomegaly characterized by hypertrophy and hyperplasia. Increased cell proliferation is implicated in the mechanism of tumor induction. The relevance of these tumors to human health is unclear. The xenoreceptors, constitutive androstane receptors (CARs), and pregnane X receptor (PXR) play key roles in these processes. Novel “humanized” and knockout models for both receptors were developed to investigate potential species differences in hepatomegaly. The effects of PB (80 mg/kg/4 days) and chlordane (10 mg/kg/4 days) were investigated in double humanized PXR and CAR (huPXR/huCAR), double knockout PXR and CAR (PXRKO/CARKO), and wild-type (WT) C57BL/6J mice. In WT mice, both compounds caused increased liver weight, hepatocellular hypertrophy, and cell proliferation. Both compounds caused alterations to a number of cell cycle genes consistent with induction of cell proliferation in WT mice. However, these gene expression changes did not occur in PXRKO/CARKO or huPXR/huCAR mice. Liver hypertrophy without hyperplasia was demonstrated in the huPXR/huCAR animals in response to both compounds. Induction of the CAR and PXR target genes, Cyp2b10 and Cyp3a11, was observed in both WT and huPXR/huCAR mouse lines following treatment with PB or chlordane. In the PXRKO/CARKO mice, neither liver growth nor induction of Cyp2b10 and Cyp3a11 was seen following PB or chlordane treatment, indicating that these effects are CAR/PXR dependent. These data suggest that the human receptors are able to support the chemically induced hypertrophic responses but not the hyperplastic (cell proliferation) responses. At this time, we cannot be certain that hCAR and hPXR when expressed in the mouse can function exactly as the genes do when they are expressed in human cells. However, all parameters investigated to date suggest that much of their functionality is maintained.
Y1  - 2010
U6  - http://dx.doi.org/10.1093/toxsci/kfq118
SN  - 1096-0929
VL  - 116
IS  - 2
SP  - 452
EP  - 466
PB  - Oxford University Press
CY  - Oxford
ER  -