@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{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}
}