@article{SalpatiChuChenetal.2014, author = {Salpati, Laurent and Chu, Xiaoyan and Chen, Liangfu and Prasad, Bhagwat and Dallas, Shannon and Evers, Raymond and Mamaril-Fishman, Donna and Geier, Ethan G. and Kehler, Jonathan and Kunta, Jeevan and Mezler, Mario and Laplanche, Loic and Pang, Jodie and Soars, Matthew G. and Unadkat, Jashvant D. and van Waterschoot, Robert A.B. and Yabut, Jocelyn and Schinkel, Alfred H. and Scheer, Nico and Rode, Anja}, title = {Evaluation of organic anion transporting polypeptide 1B1 and 1B3 humanized mice as a translational model to study the pharmacokinetics of statins}, series = {Drug Metabolism and Disposition}, volume = {42}, journal = {Drug Metabolism and Disposition}, number = {8}, publisher = {ASPET}, address = {Bethesda, Md.}, issn = {1521-009X}, doi = {10.1124/dmd.114.057976}, pages = {1301 -- 1313}, year = {2014}, abstract = {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.}, language = {en} } @article{ScheerMclaughlinRodeetal.2014, author = {Scheer, Nico and Mclaughlin, Lesley A. and Rode, Anja and MacLeod, Alastair Kenneth and Henderson, Colin J. and Wolf, Roland C.}, title = {Deletion of thirty murine cytochrome P450 genes results in viable mice with compromised drug metabolism}, series = {Drug Metabolism and Disposition}, volume = {42}, journal = {Drug Metabolism and Disposition}, number = {6}, publisher = {ASPET}, address = {Bethesda, Md.}, issn = {1521-009X}, doi = {10.1124/dmd.114.057885}, pages = {1022 -- 1030}, year = {2014}, abstract = {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.}, language = {en} } @article{ScheerBalimaneHaywardetal.2012, author = {Scheer, Nico and Balimane, Praveen and Hayward, Michael D. and Buechel, Sandra and Kauselmann, Gunther and Wolf, C. Roland}, title = {Generation and Characterization of a Novel Multidrug Resistance Protein 2 Humanized Mouse Line}, series = {Drug Metabolism and Disposition}, volume = {40}, journal = {Drug Metabolism and Disposition}, number = {11}, publisher = {ASPET}, address = {Bethesda, Md.}, issn = {1521-0111}, doi = {10.1124/dmd.112.047605}, pages = {2212 -- 2218}, year = {2012}, abstract = {The multidrug resistance protein (MRP) 2 is predominantly expressed in liver, intestine, and kidney, where it plays an important role in the excretion of a range of drugs and their metabolites or endogenous compounds into bile, feces, and urine. Mrp knockout [Mrp2(-/-)] mice have been used recently to study the role of MRP2 in drug disposition. Here, we describe the first generation and initial characterization of a mouse line humanized for MRP2 (huMRP2), which is nulled for the mouse Mrp2 gene and expresses the human transporter in the organs and cell types where MRP2 is normally expressed. Analysis of the mRNA expression for selected cytochrome P450 and transporter genes revealed no major changes in huMRP2 mice compared with wild-type controls. We show that human MRP2 is able to compensate functionally for the loss of the mouse transporter as demonstrated by comparable bilirubin levels in the humanized mice and wild-type controls, in contrast to the hyperbilirubinemia phenotype that is observed in MRP2(-/-) mice. The huMRP2 mouse provides a model to study the role of the human transporter in drug disposition and in assessing the in vivo consequences of inhibiting this transporter by compounds interacting with human MRP2.}, language = {en} } @article{ScheerKapelyukhRodeetal.2012, author = {Scheer, Nico and Kapelyukh, Yury and Rode, Anja and Buechel, Sandra and Wolf, C. Roland}, title = {Generation and characterization of novel cytochrome P450 Cyp2c gene cluster knockout and CYP2C9 humanized mouse lines}, series = {Molecular Pharmacology}, volume = {82}, journal = {Molecular Pharmacology}, number = {6}, publisher = {ASPET}, address = {Bethesda, Md.}, issn = {1521-0111}, doi = {10.1124/mol.112.080036}, pages = {1022 -- 1029}, year = {2012}, abstract = {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.}, language = {en} } @article{LempiaeinenCouttetBolognanietal.2012, author = {Lempi{\"a}inen, Harri and Couttet, Philippe and Bolognani, Federico and M{\"u}ller, Arne and Dubost, Val{\´e}rie and Luisier, Rapha{\"e}lle and Rio-Espinola, Alberto del and Vitry, Veronique and Unterberger, Elif B. and Thomson, John P. and Treindl, Fridolin and Metzger, Ute and Wrzodek, Clemens and Hahne, Florian and Zollinger, Tulipan and Brasa, Sarah and Kalteis, Magdalena and Marcellin, Magali and Giudicelli, Fanny and Braeuning, Albert and Morawiec, Laurent and Zamurovic, Natasa and L{\"a}ngle, Ulrich and Scheer, Nico and Sch{\"u}beler, Dirk and Goodman, Jay and Chibout, Salah-Dine and Marlowe, Jennifer and Theil, Dietlinde and Heard, David J. and Grenet, Olivier and Zell, Andreas and Templin, Markus F. and Meehan, Richard R. and Wolf, Roland C. and Elcombe, Clifford R. and Schwarz, Michael and Moulin, Pierre and Terranova, R{\´e}mi and Moggs, Jonathan G.}, title = {Identification of Dlk1-Dio3 imprinted gene cluster non-coding RNAs as novel candidate biomarkers for liver tumor promotion}, series = {Toxicological Sciences}, volume = {131}, journal = {Toxicological Sciences}, number = {2}, publisher = {Oxford University Press}, address = {Oxford}, issn = {1094-2025}, doi = {10.1093/toxsci/kfs303}, pages = {375 -- 386}, year = {2012}, abstract = {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.}, language = {en} } @article{KapelyukhHendersonScheeretal.2019, author = {Kapelyukh, Yury and Henderson, Colin James and Scheer, Nico and Rode, Anja and Wolf, Charles Roland}, title = {Defining the contribution of CYP1A1 and CYP1A2 to drug metabolism using humanized CYP1A1/1A2 and Cyp1a1/Cyp1a2 KO mice}, series = {Drug Metabolism and Disposition}, journal = {Drug Metabolism and Disposition}, number = {Early view}, doi = {10.1124/dmd.119.087718}, pages = {43 Seiten}, year = {2019}, language = {en} } @article{ScheerHendersonKapelyukhetal.2019, author = {Scheer, Nico and Henderson, Colin James and Kapelyukh, Yury and Rode, Anja and Mclaren, Aileen W. and MacLeod, Alastair Kenneth and Lin, De and Wright, Jayne and Stanley, Lesley and Wolf, C. Roland}, title = {An extensively humanised mouse model to predict pathways of drug disposition, drug/drug interactions, and to facilitate the design of clinical trials}, series = {Drug Metabolism and Disposition}, journal = {Drug Metabolism and Disposition}, number = {Early view}, doi = {10.1124/dmd.119.086397}, pages = {69 Seiten}, year = {2019}, language = {en} } @article{ScheerWilson2016, author = {Scheer, Nico and Wilson, Ian D.}, title = {A comparison between genetically humanized and chimeric liver humanized mouse models for studies in drug metabolism and toxicity}, series = {Drug Discovery Today}, volume = {21}, journal = {Drug Discovery Today}, number = {2}, publisher = {Elsevier}, address = {Amsterdam}, issn = {1359-6446}, doi = {10.1016/j.drudis.2015.09.002}, pages = {250 -- 263}, year = {2016}, abstract = {Mice that have been genetically humanized for proteins involved in drug metabolism and toxicity and mice engrafted with human hepatocytes are emerging and promising in vivo models for an improved prediction of the pharmacokinetic, drug-drug interaction and safety characteristics of compounds in humans. The specific advantages and disadvantages of these models should be carefully considered when using them for studies in drug discovery and development. Here, an overview on the corresponding genetically humanized and chimeric liver humanized mouse models described to date is provided and illustrated with examples of their utility in drug metabolism and toxicity studies. We compare the strength and weaknesses of the two different approaches, give guidance for the selection of the appropriate model for various applications and discuss future trends and perspectives.}, language = {en} } @article{ScheerWolf2014, author = {Scheer, Nico and Wolf, C. Roland}, title = {Genetically humanized mouse models of drug metabolizing enzymes and transporters and their applications}, series = {Xenobiotica}, volume = {44}, journal = {Xenobiotica}, number = {2}, publisher = {Taylor \& Francis}, address = {Abingdon}, issn = {1366-5928}, doi = {10.3109/00498254.2013.815831}, pages = {96 -- 108}, year = {2014}, abstract = {1. Drug metabolizing enzymes and transporters play important roles in the absorption, metabolism, tissue distribution and excretion of various compounds and their metabolites and thus can significantly affect their efficacy and safety. Furthermore, they can be involved in drug-drug interactions which can result in adverse responses, life-threatening toxicity or impaired efficacy. Significant species differences in the interaction of compounds with drug metabolizing enzymes and transporters have been described. 2. In order to overcome the limitation of animal models in accurately predicting human responses, a large variety of mouse models humanized for drug metabolizing enzymes and to a lesser extent drug transporters have been created. 3. This review summarizes the literature describing these mouse models and their key applications in studying the role of drug metabolizing enzymes and transporters in drug bioavailability, tissue distribution, clearance and drug-drug interactions as well as in human metabolite testing and risk assessment. 4. Though such humanized mouse models have certain limitations, there is great potential for their use in basic research and for testing and development of new medicines. These limitations and future potentials will be discussed.}, language = {en} } @article{ScheerWolf2013, author = {Scheer, Nico and Wolf, C. Roland}, title = {Xenobiotic receptor humanized mice and their utility}, series = {Drug Metabolism Reviews}, journal = {Drug Metabolism Reviews}, number = {1}, publisher = {Taylor \& Francis}, address = {London}, issn = {1097-9883}, doi = {10.3109/03602532.2012.738687}, pages = {110 -- 121}, year = {2013}, language = {en} } @article{HendersonScheerWolf2009, author = {Henderson, Colin J. and Scheer, Nico and Wolf, C. Roland}, title = {Advances in the generation of mouse models to elucidate the pathways of drug metabolism in rodents and man}, series = {Expert Review of Clinical Pharmacology}, volume = {2}, journal = {Expert Review of Clinical Pharmacology}, number = {2}, publisher = {Taylor \& Francis}, address = {London}, issn = {1751-2441}, doi = {10.1586/17512433.2.2.105}, pages = {105 -- 109}, year = {2009}, language = {en} } @article{StanleyHorsburghRossetal.2009, author = {Stanley, Lesley A. and Horsburgh, Brian C. and Ross, Jillian and Scheer, Nico and Wolf, C. Roland}, title = {Drug transporters: Gatekeepers controlling access of xenobiotics to the cellular interior}, series = {Drug Metabolism Reviews}, volume = {41}, journal = {Drug Metabolism Reviews}, number = {1}, publisher = {Taylor \& Francis}, address = {London}, issn = {1097-9883}, doi = {10.1080/03602530802605040}, pages = {27 -- 65}, year = {2009}, language = {en} } @article{StanleyHorsburghRossetal.2006, author = {Stanley, Lesley A. and Horsburgh, Brian C. and Ross, Jillian and Scheer, Nico and Wolf, C. Roland}, title = {Nuclear Receptors which play a pivotal role in drug disposition and chemical toxicity}, series = {Drug Metabolism Reviews}, volume = {38}, journal = {Drug Metabolism Reviews}, number = {3}, issn = {1097-9883}, doi = {10.1080/03602530600786232}, pages = {515 -- 597}, year = {2006}, language = {en} } @article{ScheerRossRodeetal.2008, author = {Scheer, Nico and Ross, Jillian and Rode, Anja and Zevnik, Branko and Niehaves, Sandra and Faust, Nicole and Wolf, C. Roland}, title = {A novel panel of mouse models to evaluate the role of human pregnane X receptor and constitutive androstane receptor in drug response}, series = {Journal of Clinical Investigation}, volume = {118}, journal = {Journal of Clinical Investigation}, number = {9}, issn = {1558-8238}, doi = {https://doi.org/10.1172/JCI35483}, pages = {3228 -- 3239}, year = {2008}, language = {en} } @article{ScheerKapelyukhMcEwanetal.2012, author = {Scheer, Nico and Kapelyukh, Yury and McEwan, Jillian and Beuger, Vincent and Stanley, Lesley A. and Rode, Anja and Wolf, C. Roland}, title = {Modeling Human Cytochrome P450 2D6 Metabolism and Drug-drug Interaction by a Novel Panel of Knockout and Humanized Mouse Lines}, series = {Molecular Pharmacology}, volume = {81}, journal = {Molecular Pharmacology}, number = {1}, publisher = {ASPET}, address = {Bethesda, Md.}, issn = {1521-0111}, doi = {10.1124/mol.111.075192}, pages = {63 -- 72}, year = {2012}, abstract = {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.}, language = {en} } @article{ReugelsBoggettiScheeretal.2006, author = {Reugels, Alexander M. and Boggetti, Barbara and Scheer, Nico and Campos-Ortega, Jos{\´e} A.}, title = {Asymmetric localization of Numb:EGFP in dividing neuroepithelial cells during neurulation in Danio rerio}, series = {Developmental Dynamics}, volume = {235}, journal = {Developmental Dynamics}, number = {4}, issn = {1097-0177}, doi = {10.1002/dvdy.20699}, pages = {934 -- 948}, year = {2006}, language = {en} } @article{HansScheerRiedletal.2004, author = {Hans, Stefan and Scheer, Nico and Riedl, Iris and Weiz{\"a}cker, Elisabeth von and Blader, Patrick and Campos-Ortega, Jos{\´e} A.}, title = {her3, a zebrafish member of the hairy-E(spl) family, is repressed by Notch signalling}, series = {Development}, volume = {131}, journal = {Development}, number = {12}, issn = {1477-9129}, doi = {10.1242/dev.01167}, pages = {2957 -- 2969}, year = {2004}, language = {en} } @article{ScheerRiedlWarrenetal.2002, author = {Scheer, Nico and Riedl, Iris and Warren, J.T. and Kuwada, John Y. and Campos-Ortega, Jos{\´e} A.}, title = {A quantitative analysis of the kinetics of Gal4 activator and effector gene expression in the zebrafish}, series = {Mechanism of Development}, volume = {112}, journal = {Mechanism of Development}, number = {1-2}, issn = {0925-4773}, doi = {10.1016/S0925-4773(01)00621-9}, pages = {9 -- 14}, year = {2002}, language = {en} } @article{LawsonScheerPhametal.2001, author = {Lawson, Nathan D. and Scheer, Nico and Pham, Van N. and Kim, Ceol-Hee and Chitnis, Ajay B. and Campos-Ortega, Jos{\´e} A. and Weinstein, Brant M.}, title = {Notch signaling is required for arterial-venous differentiation during embryonic vascular development}, series = {Development}, volume = {128}, journal = {Development}, number = {19}, issn = {1477-9129}, pages = {3675 -- 3683}, year = {2001}, language = {en} } @article{ScheerGrothHansetal.2001, author = {Scheer, Nico and Groth, Anne and Hans, Stefan and Campos-Ortega, Jos{\´e} A.}, title = {An instructive function for Notch in promoting gliogenesis in the zebrafish retina}, series = {Development}, volume = {128}, journal = {Development}, number = {7}, issn = {0950-1991}, pages = {1099 -- 1107}, year = {2001}, language = {en} }