title: Human pharmacogenetic analysis in chimeric mice with 'humanized livers'.
abstract: OBJECTIVE
  We investigated whether human pharmacogenetic factors could be characterized using chimeric NOG mice expressing a thymidine kinase transgene (TK-NOG) with 'humanized' livers.
  
  
  METHODS
  The rate of human-specific metabolism of two drugs was measured in chimeric mice reconstituted with human hepatocytes with different CYP2C19 and CYP2C9 genotypes.
  
  
  RESULTS
  The rate of generation of human-predominant drug metabolites for S-mephenytoin and diclofenac in the chimeric mice was correlated with the CYP2C19 (n=9 donors, P=0.0005) or CYP2C9 (n=7 donors, P=0.0394) genotype, respectively, of the transplanted human hepatocytes.
  
  
  CONCLUSIONS
  This study suggests that TK-NOG mice reconstituted with hepatocytes obtained from a relatively small number (3-10 per genotype) of human donors may be a promising model to identify human pharmacogenetic factors affecting the metabolism of clinically important drugs. For certain compounds, this innovative model system enables pharmacogenetic analyses to be efficiently performed in vivo within a human context and with control of all confounding environmental variables.
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Hu
authors.forename: Manhong
authors.initials: M
authors.lastname: Wu
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Nishimura
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.forename: Gary
authors.initials: G
authors.lastname: Peltz
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002352:Carrier Proteins / Q000502:physiology; D002478:Cells, Cultured; D002678:Chimera / Q000235:genetics / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D004008:Diclofenac / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism* / Q000637:transplantation; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008617:Mephenytoin / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010597:Pharmacogenetics; D013937:Thymidine Kinase / Q000502:physiology; D000099176:Noggin Protein
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D002352:Carrier Proteins; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D004008:Diclofenac; D008617:Mephenytoin; D013937:Thymidine Kinase; D000099176:Noggin Protein; C450260:CYP2C9 protein, human; C045793:CYP2C19 protein, human