Humanized PXR-CAR Mouse

Model Description

• This targeted mutation strain carries a replacement of the mouse Nr1i2 and Nr1i3 genes which encode for the nuclear receptors PXR and CAR with the corresponding human orthologous genes.
• Useful in prediction of CYP induction and therefore pharmacokinetics, drug toxicity and efficacy in man.
• Model has relevance for the prediction of the hazard of non-genotoxic rodent liver growth carcinogens to humans

Origin:
The Humanized PXR-CAR Mouse was developed by TaconicArtemis in collaboration with CXR Biosciences. The Humanized PXR Mouse model was created through a knock in of a human PXR cDNA/genomic construct onto the ATG of murine Pxr in C57BL/6NTac-derived ES cells. The human PXR sequence that was introduced contains a cDNA fusion of exon 2-4, intron 4, exon 5, intron 5, exon 6, intron 6, exon 7, intron 7, and cDNA fusion exon 8+9. The Humanized CAR Mouse model was created through a knock in of a human CAR construct containing the genomic sequence from the translational start site on exon 2 to exon 9 onto the ATG of murine CAR in C57BL/6NTac-derived ES cells. The expression of the human PXR and CAR receptors is driven by the corresponding mouse promoters. In both cases targeted ES cells were injected into BALB/cJBomTac blastocysts and the resultant chimeras were backcrossed to a Flpe deleter strain on C57BL/6J to eliminate selection markers. The Humanized PXR-CAR Mouse line was obtained by crossing the two single humanized mouse lines. Taconic received stock in 2008, and the line was embryo transfer derived. The colony is maintained by mating double homozygotes.

Color: Black

Initial Publication:

Scheer N, Ross J, Rode A, Zevnik B, Niehaves S, Faust N, Wolf CR. (2008) A novel panel of mouse models to evaluate the role of human pregnane X receptor and constitutive androstane receptor in drug response. J. Clin. Invest. 118(9): 3228-3239.

Note: This publication describes only the humanized CAR modification. An improved PXR humanized model was created subsequent to this publication (see reference below), and it was used to create the present Humanized PXR-CAR Mouse model. The original humanized PXR model expressed an aberrant splice variant in addition to the splice variants known to be expressed in humans, meaning that a fraction of the mRNA expressed by this model did not code for a functional protein. This led to a reduced responsiveness to PXR activators. The improved humanized PXR model, which was used to create model 8223, exclusively expresses the known human splice variants, and compared to the original humanized PXR model, shows a higher responsiveness to PXR activators.

Scheer N, Ross J, Kapelyukh Y, Rode A, Wolf CR. (2010). In vivo responses of the human and murine pregnane X receptor to dexamethasone in mice. Drug Metab Disp Epub ahead of print.

Animal Diet: NIH #31M Rodent Diet

Licensing Requirements:

Non-profit users (excluding users at non-profit foundations which are affiliated with a for-profit entity): Taconic Non-Profit MTA

Pricing for non-profit users (excluding users at non-profit foundations which are affiliated with a for-profit entity):

8223

Humanized PXR-CAR Mouse European prices for non-profit users

For-profit users (including users at non-profit foundations which are affiliated with a for-profit entity): Taconic For-Profit MTA

Pricing for for-profit users (including users at non-profit foundations which are affiliated with a for-profit entity):

8223

Humanized PXR-CAR Mouse European prices for for-profit users

Availability: Immediate availability of appropriately-sized cohorts.

Health Reports/Production Sites

View the production locations(s) and the accompanying current IHMS^TM Health Report and Taconic Health Standard for this model

Contact Us or call:

• 888.TACONIC (822.6642)
• Fax: 518.697.3910
• +45 70 23 04 05 (Europe)