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 - 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 - Snaith, Mike A1 - Wolf, C. Roland A1 - Seibler, Jost T1 - Generation and utility of genetically humanized mouse models JF - Drug Discovery Today Y1 - 2013 U6 - http://dx.doi.org/10.1016/j.drudis.2013.07.007 SN - 1359-6446 VL - Vol 18 IS - 23-24 SP - 1200 EP - 1211 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Lassonczyk, Beate A1 - Alaily, F. A1 - Huth, A. A1 - Gensior, A. T1 - Genesis of soils in the arid part of northeast Somalia / F. Alaily, B. Lassonczyk, A.Huth and A. Gensior JF - Berliner geowissenschaftliche Abhandlungen / Reihe A, Geologie und Paläontologie / hrsg. von d. Geowissenschaftlichen Instituten der Freien u. d. Technischen Universität Berlin. 120 A (1990) Y1 - 1990 SN - 0172-8784 SP - 695 EP - 711 ER - TY - JOUR A1 - Borgmeier, Claudia A1 - Bongaerts, Johannes A1 - Meinhardt, Friedhelm T1 - Genetic analysis of the Bacillus licheniformis degSU operon and the impact of regulatory mutations on protease production JF - Journal of biotechnology N2 - Disruption experiments targeted at the Bacillus licheniformis degSU operon and GFP-reporter analysis provided evidence for promoter activity immediately upstream of degU. pMutin mediated concomitant introduction of the degU32 allele – known to cause hypersecretion in Bacillus subtilis – resulted in a marked increase in protease activity. Application of 5-fluorouracil based counterselection through establishment of a phosphoribosyltransferase deficient Δupp strain eventually facilitated the marker-free introduction of degU32 leading to further protease enhancement achieving levels as for hypersecreting wild strains in which degU was overexpressed. Surprisingly, deletion of rapG – known to interfere with DegU DNA-binding in B. subtilis – did not enhance protease production neither in the wild type nor in the degU32 strain. The combination of degU32 and Δupp counterselection in the type strain is not only equally effective as in hypersecreting wild strains with respect to protease production but furthermore facilitates genetic strain improvement aiming at biological containment and effectiveness of biotechnological processes. KW - Marker-free mutagenesis KW - Extracellular enzymes KW - Uracil-phosphoribosyltransferase KW - Hypersecretion Y1 - 2012 U6 - http://dx.doi.org/10.1016/j.jbiotec.2012.02.011 SN - 1873-4863 (E-Journal); 0168-1656 (Print) VL - 159 IS - 1-2 SP - 12 EP - 20 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Deppe, Veronika Maria A1 - Klatte, Stephanie A1 - Bongaerts, Johannes A1 - Maurer, Karl-Heinz A1 - O'Connell, Timothy A1 - Meinhardt, Friedhelm T1 - Genetic control of Amadori product degradation in Bacillus subtilis via regulation of frlBONMD expression by FrlR JF - Applied and environmental microbiology Y1 - 2011 SN - 1098-5336 (E-Journal); 0003-6919 (Print); 0099-2240 (Print) VL - Vol. 77 IS - No. 9 SP - 2839 EP - 2846 PB - American Society of Mechanical Engineers (ASME) CY - New York ER - TY - JOUR A1 - Medlin, L. K. A1 - Lange, M. A1 - Baumann, Marcus T1 - Genetic differentiation among three colony-forming species of Phaeocystis : further evidence for the phylogeny of the Prymnesiophyta JF - Phycologia Y1 - 1994 SN - 0031-8884 VL - Vol. 33 IS - Iss. 3 SP - 199 EP - 212 ER - TY - JOUR A1 - Scheer, Nico A1 - Wolf, C. Roland T1 - Genetically humanized mouse models of drug metabolizing enzymes and transporters and their applications JF - Xenobiotica N2 - 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. KW - transporters KW - human metabolites KW - drug metabolising enzymes KW - drug–drug interactions KW - bioavailability Y1 - 2014 U6 - http://dx.doi.org/10.3109/00498254.2013.815831 SN - 1366-5928 VL - 44 IS - 2 SP - 96 EP - 108 PB - Taylor & Francis CY - Abingdon ER - TY - JOUR A1 - Waller, Mark P. A1 - Braun, Heiko A1 - Hojdis, Nils A1 - Bühl, Michael T1 - Geometries of Second-Row Transition-Metal Complexes from Density-Functional Theory JF - Journal of Chemical Theory and Computation Y1 - 2007 U6 - http://dx.doi.org/10.1021/ct700178y SN - 1549-9626 VL - 3 IS - 6 SP - 2234 EP - 2242 ER - TY - JOUR A1 - Kotter, Michael A1 - Hammon, Ulrich A1 - Riekert, Lothar T1 - Gewinnung niedriger Olefine aus Methanol bei partiellem Umsatz mit Rückführung / U. Hammon ; M. Kotter ; L. Riekert JF - Chemie - Ingenieur - Technik. 61 (1989), H. 2 Y1 - 1989 SN - 0009-286X N1 - ISSN der E-Ausg.: 1522-2640 SP - 151 EP - 152 ER -