TY  - JOUR
A1  - Seibler, Jost
A1  - Zevnik, Branko
A1  - Küter-Luks, Birgit
A1  - Andreas, Susanne
A1  - Kern, Heidrun
A1  - Hennek, Thomas
A1  - Rode, Anja
A1  - Heimann, Cornelia
A1  - Faust, Nicole
A1  - Kauselmann, Gunther
A1  - Schoor, Michael
A1  - Jaenisch, Rudolf
A1  - Rajewsky, Klaus
A1  - Kühn, Ralf
A1  - Schwenk, Frieder
T1  - Rapid generation of inducible mouse mutants
JF  - Nucleic Acids Research
Y1  - 2003
U6  - http://dx.doi.org/10.1093/nar/gng012
SN  - 1362-4962
VL  - 33
IS  - 4
SP  - e12
ER  - 
TY  - JOUR
A1  - Scheer, Nico
A1  - Ross, Jillian
A1  - Rode, Anja
A1  - Zevnik, Branko
A1  - Niehaves, Sandra
A1  - Faust, Nicole
A1  - Wolf, C. Roland
T1  - A novel panel of mouse models to evaluate the role of human pregnane X receptor and constitutive androstane receptor in drug response
JF  - Journal of Clinical Investigation
Y1  - 2008
U6  - http://dx.doi.org/https://doi.org/10.1172/JCI35483
SN  - 1558-8238
VL  - 118
IS  - 9
SP  - 3228
EP  - 3239
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  - 
TY  - JOUR
A1  - Scheer, Nico
A1  - Ross, Jillian
A1  - Kapelyukh, Yury
A1  - Rode, Anja
A1  - Wolf, C. Roland
T1  - In vivo responses of the human and murine pregnane X receptor to dexamethasone in mice
JF  - Drug Metabolism and Disposition
N2  - Dexamethasone (DEX) is a potent and widely used anti-inflammatory and immunosuppressant glucocorticoid. It can bind and activate the pregnane X receptor (PXR), which plays a critical role as xenobiotic sensor in mammals to induce the expression of many enzymes, including cytochromes P450 in the CYP3A family. This induction results in its own metabolism. We have used a series of transgenic mouse lines, including a novel, improved humanized PXR line, to compare the induction profile of PXR-regulated drug-metabolizing enzymes after DEX administration, as well as looking at hepatic responses to rifampicin (RIF). The new humanized PXR model has uncovered further intriguing differences between the human and mouse receptors in that RIF only induced Cyp2b10 in the new humanized model. DEX was found to be a much more potent inducer of Cyp3a proteins in wild-type mice than in mice humanized for PXR. To assess whether PXR is involved in the detoxification of DEX in the liver, we analyzed the consequences of high doses of the glucocorticoid on hepatotoxicity on different PXR genetic backgrounds. We also studied these effects in an additional mouse model in which functional mouse Cyp3a genes have been deleted. These strains exhibited different sensitivities to DEX, indicating a protective role of the PXR and CYP3A proteins against the hepatotoxicity of this compound.
Y1  - 2010
U6  - http://dx.doi.org/10.1124/dmd.109.031872
SN  - 1521-009X
VL  - 38
IS  - 7
SP  - 1046
EP  - 1053
PB  - ASPET
CY  - Bethesda
ER  - 
TY  - JOUR
A1  - Hasegawa, Maki
A1  - Kapelyukh, Yury
A1  - Tahara, Harunobu
A1  - Seibler, Jost
A1  - Rode, Anja
A1  - Krueger, Sylvia
A1  - Lee, Dongtao N.
A1  - Wolf, C. Roland
A1  - Scheer, Nico
T1  - Quantitative prediction of human pregnane X receptor and cytochrome P450 3A4 mediated drug-drug interaction in a novel multiple humanized mouse line
JF  - Molecular Pharmacology
Y1  - 2011
U6  - http://dx.doi.org/10.1124/mol.111.071845
SN  - 1521-0111
VL  - 80
IS  - 33
SP  - 518
EP  - 528
PB  - ASPET
CY  - Bethesda, Md.
ER  - 
TY  - JOUR
A1  - Scheer, Nico
A1  - Kapelyukh, Yury
A1  - Rode, Anja
A1  - Buechel, Sandra
A1  - Wolf, C. Roland
T1  - Generation and characterization of novel cytochrome P450 Cyp2c gene cluster knockout and CYP2C9 humanized mouse lines
JF  - Molecular Pharmacology
N2  - Compared with rodents and many other animal species, the human cytochrome P450 (P450) Cyp2c gene cluster varies significantly in the multiplicity of functional genes and in the substrate specificity of its enzymes. As a consequence, the use of wild-type animal models to predict the role of human CYP2C enzymes in drug metabolism and drug-drug interactions is limited. Within the human CYP2C cluster CYP2C9 is of particular importance, because it is one of the most abundant P450 enzymes in human liver, and it is involved in the metabolism of a wide variety of important drugs and environmental chemicals. To investigate the in vivo functions of cytochrome P450 Cyp2c genes and to establish a model for studying the functions of CYP2C9 in vivo, we have generated a mouse model with a deletion of the murine Cyp2c gene cluster and a corresponding humanized model expressing CYP2C9 specifically in the liver. Despite the high number of functional genes in the mouse Cyp2c cluster and the reported roles of some of these proteins in different biological processes, mice deleted for Cyp2c genes were viable and fertile but showed certain phenotypic alterations in the liver. The expression of CYP2C9 in the liver also resulted in viable animals active in the metabolism and disposition of a number of CYP2C9 substrates. These mouse lines provide a powerful tool for studying the role of Cyp2c genes and of CYP2C9 in particular in drug disposition and as a factor in drug-drug interaction.
Y1  - 2012
U6  - http://dx.doi.org/10.1124/mol.112.080036
SN  - 1521-0111
VL  - 82
IS  - 6
SP  - 1022
EP  - 1029
PB  - ASPET
CY  - Bethesda, Md.
ER  - 
TY  - JOUR
A1  - Scheer, Nico
A1  - Kapelyukh, Yury
A1  - McEwan, Jillian
A1  - Beuger, Vincent
A1  - Stanley, Lesley A.
A1  - Rode, Anja
A1  - Wolf, C. Roland
T1  - Modeling Human Cytochrome P450 2D6 Metabolism and Drug-drug Interaction by a Novel Panel of Knockout and Humanized Mouse Lines
JF  - Molecular Pharmacology
N2  - The highly polymorphic human cytochrome P450 2D6 enzyme is involved in the metabolism of up to 25% of all marketed drugs and accounts for significant individual differences in response to CYP2D6 substrates. Because of the differences in the multiplicity and substrate specificity of CYP2D family members among species, it is difficult to predict pathways of human CYP2D6-dependent drug metabolism on the basis of animal studies. To create animal models that reflect the human situation more closely and that allow an in vivo assessment of the consequences of differential CYP2D6 drug metabolism, we have developed a novel straightforward approach to delete the entire murine Cyp2d gene cluster and replace it with allelic variants of human CYP2D6. By using this approach, we have generated mouse lines expressing the two frequent human protein isoforms CYP2D6.1 and CYP2D6.2 and an as yet undescribed variant of this enzyme, as well as a Cyp2d cluster knockout mouse. We demonstrate that the various transgenic mouse lines cover a wide spectrum of different human CYP2D6 metabolizer phenotypes. The novel humanization strategy described here provides a robust approach for the expression of different CYP2D6 allelic variants in transgenic mice and thus can help to evaluate potential CYP2D6-dependent interindividual differences in drug response in the context of personalized medicine.
Y1  - 2012
U6  - http://dx.doi.org/10.1124/mol.111.075192
SN  - 1521-0111
VL  - 81
IS  - 1
SP  - 63
EP  - 72
PB  - ASPET
CY  - Bethesda, Md.
ER  - 
TY  - JOUR
A1  - Salpati, Laurent
A1  - Chu, Xiaoyan
A1  - Chen, Liangfu
A1  - Prasad, Bhagwat
A1  - Dallas, Shannon
A1  - Evers, Raymond
A1  - Mamaril-Fishman, Donna
A1  - Geier, Ethan G.
A1  - Kehler, Jonathan
A1  - Kunta, Jeevan
A1  - Mezler, Mario
A1  - Laplanche, Loic
A1  - Pang, Jodie
A1  - Soars, Matthew G.
A1  - Unadkat, Jashvant D.
A1  - van Waterschoot, Robert A.B.
A1  - Yabut, Jocelyn
A1  - Schinkel, Alfred H.
A1  - Scheer, Nico
A1  - Rode, Anja
T1  - Evaluation of organic anion transporting polypeptide 1B1 and 1B3 humanized mice as a translational model to study the pharmacokinetics of statins
JF  - Drug Metabolism and Disposition
N2  - Organic anion transporting polypeptide (Oatp) 1a/1b knockout and OATP1B1 and -1B3 humanized mouse models are promising tools for studying the roles of these transporters in drug disposition. Detailed characterization of these models will help to better understand their utility for predicting clinical outcomes. To advance this approach, we carried out a comprehensive analysis of these mouse lines by evaluating the compensatory changes in mRNA expression, quantifying the amounts of OATP1B1 and -1B3 protein by liquid chromatography–tandem mass spectrometry, and studying the active uptake in isolated hepatocytes and the pharmacokinetics of some prototypical substrates including statins. Major outcomes from these studies were 1) mostly moderate compensatory changes in only a few genes involved in drug metabolism and disposition, 2) a robust hepatic expression of OATP1B1 and -1B3 proteins in the respective humanized mouse models, and 3) functional activities of the human transporters in hepatocytes isolated from the humanized models with several substrates tested in vitro and with pravastatin in vivo. However, the expression of OATP1B1 and -1B3 in the humanized models did not significantly alter liver or plasma concentrations of rosuvastatin and pitavastatin compared with Oatp1a/1b knockout controls under the conditions used in our studies. Hence, although the humanized OATP1B1 and -1B3 mice showed in vitro and/or in vivo functional activity with some statins, further characterization of these models is required to define their potential use and limitations in the prediction of drug disposition and drug-drug interactions in humans.
Y1  - 2014
U6  - http://dx.doi.org/10.1124/dmd.114.057976
SN  - 1521-009X
VL  - 42
IS  - 8
SP  - 1301
EP  - 1313
PB  - ASPET
CY  - Bethesda, Md.
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  - 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  - Dallas, Shannon
A1  - Salphati, Laurent
A1  - Gomez-Zepeda, David
A1  - Wanek, Thomas
A1  - Chen, Liangfu
A1  - Chu, Xiaoyan
A1  - Kunta, Jeevan
A1  - Mezler, Mario
A1  - Menet, Marie-Claude
A1  - Chasseigneaux, Stephanie
A1  - Declèves, Xavier
A1  - Langer, Oliver
A1  - Pierre, Esaie
A1  - DiLoreto, Karen
A1  - Hoft, Carolin
A1  - Laplanche, Loic
A1  - Pang, Jodie
A1  - Pereira, Tony
A1  - Andonian, Clara
A1  - Simic, Damir
A1  - Rode, Anja
A1  - Yabut, Jocelyn
A1  - Zhang, Xiaolin
A1  - Scheer, Nico
T1  - Generation and Characterization of a Breast Cancer Resistance Protein Humanized Mouse Model
JF  - Molecular Pharmacology
N2  - Breast cancer resistance protein (BCRP) is expressed in various tissues, such as the gut, liver, kidney and blood brain barrier (BBB), where it mediates the unidirectional transport of substrates to the apical/luminal side of polarized cells. Thereby BCRP acts as an efflux pump, mediating the elimination or restricting the entry of endogenous compounds or xenobiotics into tissues and it plays important roles in drug disposition, efficacy and safety. Bcrp knockout mice (Bcrp−/−) have been used widely to study the role of this transporter in limiting intestinal absorption and brain penetration of substrate compounds. Here we describe the first generation and characterization of a mouse line humanized for BCRP (hBCRP), in which the mouse coding sequence from the start to stop codon was replaced with the corresponding human genomic region, such that the human transporter is expressed under control of the murine Bcrp promoter. We demonstrate robust human and loss of mouse BCRP/Bcrp mRNA and protein expression in the hBCRP mice and the absence of major compensatory changes in the expression of other genes involved in drug metabolism and disposition. Pharmacokinetic and brain distribution studies with several BCRP probe substrates confirmed the functional activity of the human transporter in these mice. Furthermore, we provide practical examples for the use of hBCRP mice to study drug-drug interactions (DDIs). The hBCRP mouse is a promising model to study the in vivo role of human BCRP in limiting absorption and BBB penetration of substrate compounds and to investigate clinically relevant DDIs involving BCRP.
Y1  - 2016
U6  - http://dx.doi.org/10.1124/mol.115.102079
SN  - 1521-0111
VL  - 89
IS  - 5
SP  - 492
EP  - 504
PB  - ASPET
CY  - Bethesda, Md.
ER  - 
TY  - JOUR
A1  - Kapelyukh, Yury
A1  - Henderson, Colin James
A1  - Scheer, Nico
A1  - Rode, Anja
A1  - Wolf, Charles Roland
T1  - Defining the contribution of CYP1A1 and CYP1A2 to drug metabolism using humanized CYP1A1/1A2 and Cyp1a1/Cyp1a2 KO mice
JF  - Drug Metabolism and Disposition
Y1  - 2019
U6  - http://dx.doi.org/10.1124/dmd.119.087718
IS  - Early view
ER  - 
TY  - JOUR
A1  - Scheer, Nico
A1  - Henderson, Colin James
A1  - Kapelyukh, Yury
A1  - Rode, Anja
A1  - Mclaren, Aileen W.
A1  - MacLeod, Alastair Kenneth
A1  - Lin, De
A1  - Wright, Jayne
A1  - Stanley, Lesley
A1  - Wolf, C. Roland
T1  - An extensively humanised mouse model to predict pathways of drug disposition, drug/drug interactions, and to facilitate the design of clinical trials
JF  - Drug Metabolism and Disposition
Y1  - 2019
U6  - http://dx.doi.org/10.1124/dmd.119.086397
IS  - Early view
ER  -