Humanized OATP1B1 Mouse

Constitutive Knock Out

Humanized OATP1B1 Constitutive Knock Out Mouse Model

FVB Background

  • Model #
  • Genotype
  • Nomenclature
  • 10708-F
    ko/ko;tg/tg
    FVB.129P2-Del(Slco1b2-Slco1a5)1Ahs Tg(APOE-SLCO1B1)1Ahs
  • 10708-M
    ko/ko;tg/tg
    FVB.129P2-Del(Slco1b2-Slco1a5)1Ahs Tg(APOE-SLCO1B1)1Ahs
  • This model carries a deletion of all five established Slco1a and 1b and two predicted Slco1a-like mouse genes as well as a random transgenic insertion of human SLCO1B1 (OATP1B1) under control of liver specific ApoE promoter.
  • Contains a cre-mediated deletion of the following established genes in the Slco1a/1b cluster: Slco1a1, Slco1a4, Slco1a5, Slco1a6, and Slco1b2.
  • SLCO1B1 (OATP1B1) is an important hepatic uptake transporter that can transport a wide variety of drugs, such as many statins.
  • Useful in dissecting the role of human OATP1B1 in hepatic liver uptake, drug-drug interaction and drug toxicity.

Genetic Background:

FVB/N Background

Origin:

The Oatp1a/1b Cluster Knockout Mouse was developed in the laboratory of Alfred Schinkel of the Netherlands Cancer Institute in 2010. The model was generated by insertion?of?loxP?sites?into the Slco1a5 and Slco1b2 genes at?both?ends?of?the?Slco1a/1b?gene?cluster in E14 embryonic stem cells derived from 129P2/OlaHsd mice, followed by Cre-mediated?deletion and injecting the targeted cells into C57BL/6J blastocysts. Resultant chimeras were backcrossed to FVB/N mice. Expression of human OATP1B1 in the liver of transgenic mice was achieved by constructing an ApoE promoter-HCR1-driven expression cassette containing human SLCO1B1 cDNA followed by pronuclear injection into fertilized oocytes of FVB mice. Two-cell stage embryos were implanted into oviducts of pseudopregnant F1 fosters and carried to term. A founder with stable hepatic expression of human OATP1B1 was selected for further crosses with Oatp1a/1b Cluster Knockout Mouse described above. Taconic received stock in 2010. The mice were derived by embryo transfer and are maintained by incrossing of mice homozygous for both the Oatp1a/1b Cluster Knockout and the human OATP1B1 transgene.


Genetics:

Wildtype for Nnt mutation; carries Pde6brd1 mutation


Color:

Albino

Species:

Mouse

Initial Publication:

van de Steeg E, van Esch A, Wagenaar E, Kenworthy KE, Schinkel AH (2012). Influence of human OATP1B1, OATP1B3, and OATP1A2 on the pharmacokinetics of methotrexate and paclitaxel in humanized transgenic mice. Clin Cancer Res. 2012 Dec 14.

van de Steeg E, Stránecký V, Hartmannová H, Nosková L, Høebíèek M, Wagenaar E, van Esch A, de Waart DR, Oude Elferink RP, Kenworthy KE, Sticová E, Al-Edreesi M, Knisely AS, Kmoch S, Jirsa M, Schinkel AH (2012). Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J. Clin. Invest. 122 (2) 519-28.

 



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