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  - 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  - Scheer, Nico
A1  - Riedl, Iris
A1  - Warren, J.T.
A1  - Kuwada, John Y.
A1  - Campos-Ortega, José A.
T1  - A quantitative analysis of the kinetics of Gal4 activator and effector gene expression in the zebrafish
JF  - Mechanism of Development
Y1  - 2002
U6  - http://dx.doi.org/10.1016/S0925-4773(01)00621-9
SN  - 0925-4773
VL  - 112
IS  - 1-2
SP  - 9
EP  - 14
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  - 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  - 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  - 
TY  - JOUR
A1  - Scheer, Nico
A1  - Groth, Anne
A1  - Hans, Stefan
A1  - Campos-Ortega, José A.
T1  - An instructive function for Notch in promoting gliogenesis in the zebrafish retina
JF  - Development
Y1  - 2001
SN  - 0950-1991
VL  - 128
IS  - 7
SP  - 1099
EP  - 1107
ER  - 
TY  - CHAP
A1  - Scheer, Nico
A1  - Chu, Xiaoyan
A1  - Salphati, Laurent
A1  - Zamek-Gliszczynski, Maciej J.
ED  - Nicholls, Glynis
T1  - Knockout and humanized animal models to study membrane transporters in drug development
T2  - Drug Transporters: Volume 1: Role and Importance in ADME and Drug Development
Y1  - 2016
SN  - 978-1-78262-379-3
U6  - http://dx.doi.org/10.1039/9781782623793-00298
SP  - 298
EP  - 332
PB  - Royal Society of Chemistry
CY  - Cambridge
ER  - 
TY  - JOUR
A1  - Scheer, Nico
A1  - Campos-Ortega, José A.
T1  - Use of the Gal4-UAS technique for targeted gene expression in the zebrafish
JF  - Mechanism of Development
Y1  - 1999
U6  - http://dx.doi.org/10.1016/S0925-4773(98)00209-3
SN  - 0925-4773
VL  - 80
IS  - 2
SP  - 153
EP  - 158
ER  - 
TY  - JOUR
A1  - Scheer, Nico
A1  - Balimane, Praveen
A1  - Hayward, Michael D.
A1  - Buechel, Sandra
A1  - Kauselmann, Gunther
A1  - Wolf, C. Roland
T1  - Generation and Characterization of a Novel Multidrug Resistance Protein 2 Humanized Mouse Line
JF  - Drug Metabolism and Disposition
N2  - 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.
Y1  - 2012
U6  - http://dx.doi.org/10.1124/dmd.112.047605
SN  - 1521-0111
VL  - 40
IS  - 11
SP  - 2212
EP  - 2218
PB  - ASPET
CY  - Bethesda, Md.
ER  - 
TY  - JOUR
A1  - Scheele, Sandra
A1  - Oertel, Dan
A1  - Bongaerts, Johannes
A1  - Evers, Stefan
A1  - Hellmuth, Hendrik
A1  - Maurer, Karl-Heinz
A1  - Bott, Michael
A1  - Freudl, Roland
T1  - Secretory production of an FAD cofactor-containing cytosolic enzyme (sorbitol–xylitol oxidase from Streptomyces coelicolor) using the twin-arginine translocation (Tat) pathway of Corynebacterium glutamicum
JF  - Microbial biotechnology
Y1  - 2013
SN  - 1751-7915
SP  - 202
EP  - 206
PB  - Wiley-Blackwell
CY  - Oxford
ER  - 
TY  - CHAP
A1  - Samuelsson, K.
A1  - Scheer, Nico
A1  - Wilson, I.
A1  - Wolf, C.R.
A1  - Henderson, C.J.
ED  - Chackalamannil, Samuel
T1  - Genetically Humanized Animal Models
T2  - Comprehensive Medicinal Chemistry III. 3rd Edition
N2  - Genetically humanized mice for proteins involved in drug metabolism and toxicity and mice engrafted with human hepatocytes are emerging as promising in vivo models for improved prediction of the pharmacokinetic, drug–drug interaction, and safety characteristics of compounds in humans. This is an overview on the genetically humanized and chimeric liver-humanized mouse models, which are illustrated with examples of their utility in drug metabolism and toxicity studies. The models are compared to give guidance for selection of the most appropriate model by highlighting advantages and disadvantages to be carefully considered when used for studies in drug discovery and development.
KW  - Chimeric liver-humanized mice
KW  - Drug distribution
KW  - Drug metabolism
KW  - Toxicology
KW  - Knockout mice
Y1  - 2017
SN  - 978-0-12-803201-5
U6  - http://dx.doi.org/10.1016/B978-0-12-409547-2.12376-5
SP  - 130
EP  - 149
PB  - Elsevier
CY  - Saint Louis
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  - Rösch, C.
A1  - Kratz, F.
A1  - Hering, T.
A1  - Trautmann, S.
A1  - Umanskaya, N.
A1  - Tippkötter, Nils
A1  - Müller-Renno, C.M.
A1  - Ulber, R.
A1  - Hannig, M.
A1  - Ziegler, C.
T1  - Albumin-lysozyme interactions: cooperative adsorption on titanium and enzymatic activity
JF  - Colloids and Surfaces B: Biointerfaces
N2  - The interplay of albumin (BSA) and lysozyme (LYZ) adsorbed simultaneously on titanium was analyzed by gel electrophoresis and BCA assay. It was found that BSA and lysozyme adsorb cooperatively. Additionally, the isoelectric point of the respective protein influences the adsorption. Also, the enzymatic activity of lysozyme and amylase (AMY) in mixtures with BSA was considered with respect to a possible influence of protein-protein interaction on enzyme activity. Indeed, an increase of lysozyme activity in the presence of BSA could be observed. In contrast, BSA does not influence the activity of amylase.
Y1  - 2016
U6  - http://dx.doi.org/10.1016/j.colsurfb.2016.09.048
VL  - 149
IS  - 1
SP  - 115
EP  - 121
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Röhlen, Desiree
A1  - Pilas, Johanna
A1  - Schöning, Michael Josef
A1  - Selmer, Thorsten
T1  - Development of an amperometric biosensor platform for the combined determination of l-Malic, Fumaric, and l-Aspartic acid
JF  - Applied Biochemistry and Biotechnology
N2  - Three amperometric biosensors have been developed for the detection of L-malic acid, fumaric acid, and L -aspartic acid, all based on the combination of a malate-specific dehydrogenase (MDH, EC 1.1.1.37) and diaphorase (DIA, EC 1.8.1.4). The stepwise expansion of the malate platform with the enzymes fumarate hydratase (FH, EC 4.2.1.2) and aspartate ammonia-lyase (ASPA, EC 4.3.1.1) resulted in multi-enzyme reaction cascades and, thus, augmentation of the substrate spectrum of the sensors. Electrochemical measurements were carried out in presence of the cofactor β-nicotinamide adenine dinucleotide (NAD+) and the redox mediator hexacyanoferrate (III) (HCFIII). The amperometric detection is mediated by oxidation of hexacyanoferrate (II) (HCFII) at an applied potential of + 0.3 V vs. Ag/AgCl. For each biosensor, optimum working conditions were defined by adjustment of cofactor concentrations, buffer pH, and immobilization procedure. Under these improved conditions, amperometric responses were linear up to 3.0 mM for L-malate and fumarate, respectively, with a corresponding sensitivity of 0.7 μA mM−1 (L-malate biosensor) and 0.4 μA mM−1 (fumarate biosensor). The L-aspartate detection system displayed a linear range of 1.0–10.0 mM with a sensitivity of 0.09 μA mM−1. The sensor characteristics suggest that the developed platform provides a promising method for the detection and differentiation of the three substrates.
Y1  - 2017
U6  - http://dx.doi.org/10.1007/s12010-017-2578-1
SN  - 1559-0291
VL  - 183
SP  - 566
EP  - 581
PB  - Springer
CY  - Berlin
ER  - 
TY  - JOUR
A1  - Röhlen, Desiree
A1  - Pilas, Johanna
A1  - Dahmen, Markus
A1  - Keusgen, Michael
A1  - Selmer, Thorsten
A1  - Schöning, Michael Josef
T1  - Toward a Hybrid Biosensor System for Analysis of Organic and Volatile Fatty Acids in Fermentation Processes
JF  - Frontiers in Chemistry
N2  - Monitoring of organic acids (OA) and volatile fatty acids (VFA) is crucial for the control of anaerobic digestion. In case of unstable process conditions, an accumulation of these intermediates occurs. In the present work, two different enzyme-based biosensor arrays are combined and presented for facile electrochemical determination of several process-relevant analytes. Each biosensor utilizes a platinum sensor chip (14 × 14 mm²) with five individual working electrodes. The OA biosensor enables simultaneous measurement of ethanol, formate, d- and l-lactate, based on a bi-enzymatic detection principle. The second VFA biosensor provides an amperometric platform for quantification of acetate and propionate, mediated by oxidation of hydrogen peroxide. The cross-sensitivity of both biosensors toward potential interferents, typically present in fermentation samples, was investigated. The potential for practical application in complex media was successfully demonstrated in spiked sludge samples collected from three different biogas plants. Thereby, the results obtained by both of the biosensors were in good agreement to the applied reference measurements by photometry and gas chromatography, respectively. The proposed hybrid biosensor system was also used for long-term monitoring of a lab-scale biogas reactor (0.01 m³) for a period of 2 months. In combination with typically monitored parameters, such as gas quality, pH and FOS/TAC (volatile organic acids/total anorganic carbonate), the amperometric measurements of OA and VFA concentration could enhance the understanding of ongoing fermentation processes.
Y1  - 2018
U6  - http://dx.doi.org/10.3389/fchem.2018.00284
IS  - 6
PB  - Frontiers
CY  - Lausanne
ER  - 
TY  - JOUR
A1  - Roth, Jasmine
A1  - Tippkötter, Nils
T1  - Evaluation of lignocellulosic material for butanol production using enzymatic hydrolysate medium
JF  - Cellulose Chemistry and Technology
N2  - Butanol is a promising gasoline additive and platform chemical that can be readily produced via acetone-butanolethanol (ABE) fermentation from pretreated lignocellulosic materials. This article examines lignocellulosic material from beech wood for ABE fermentation, using Clostridium acetobutylicum. First, the utilization of both C₅₋ (xylose) and C₆₋ (glucose) sugars as sole carbon source was investigated in static cultivation, using serum bottles and synthetic medium. The utilization of pentose sugar resulted in a solvent yield of 0.231 g·g_sugar⁻¹, compared to 0.262 g·g_sugar⁻¹ using hexose. Then, the Organosolv pretreated crude cellulose fibers (CF) were enzymatically decomposed, and the resulting hydrolysate medium was analyzed for inhibiting compounds (furans, organic acids, phenolics) and treated with ionexchangers for detoxification. Batch fermentation in a bioreactor using CF hydrolysate medium resulted in a total solvent yield of 0.20 gABE·g_sugar⁻¹.
Y1  - 2016
VL  - 50
IS  - 3-4
SP  - 405
EP  - 410
PB  - Editura Academiei Romane
CY  - Bukarest
ER  - 
TY  - CHAP
A1  - Roth, J.
A1  - Möhring, S.
A1  - Tippkötter, Nils
T1  - Characterization and evaluation of lignocellulosic biomass 130 hydrolysates for ABE fermentation
T2  - New frontiers of biotech-processes (Himmelfahrtstagung) : 02-04 May 2016, Rhein-Mosel-Halle, Koblenz/Germany
Y1  - 2016
SP  - 130
PB  - DECHEMA
CY  - Frankfurt am Main
ER  -