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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, as well as a a replacement of seven full-length mouse Cyp3a genes (Cyp3a11, Cyp3a16, Cyp3a25, Cyp3a41, Cyp3a44, Cyp3a57, Cyp3a59) with approximately 125 kb of genomic human DNA comprising CYP3A4 and CYP3A7.
CYP3A4 is the most abundant hepatic and intestinal CYP in humans and catalyzes the metabolism of more than 50% of drugs in clinical use and its expression is regulated by PXR and CAR.
Useful in prediction of CYP induction and therefore pharmacokinetics, drug toxicity and efficacy in humans.
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Genetic Background: C57BL/6 Background
The Humanized PXR-CAR-CYP3A4/3A7 Mouse was developed by Taconic 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. The Humanized CYP3A4/3A7 Mouse model was created by four consecutive rounds of transfection in C57BL/6NTac-derived ES cells. First, mouse exon 1 and 2 of Cyp3a57 was replaced with a hygromycin cassette containing a loxP, lox5171 and frt site through gene targeting. Second, a neomycin cassette with a loxP and f3 site was inserted into intron 4 of the Cyp3a59 gene through gene targeting. Third, transfection of the ES cells with cre recombinase resulted in the deletion of the Cyp3a57, Cyp3a16, Cyp3a41, Cyp3a44, Cyp3a11, Cyp3a25 and Cyp3a59 genes. Fourth, a modified human bacterial artificial chromosome carrying CYP3A4 and CYP3A7 was inserted by cre-mediated recombination into the loxP and lox5171 sites in the mouse Cyp3a locus. In all three 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-CYP3A4/3A7 Mouse line was obtained by crossing the three single humanized mouse lines. The colony was maintained by mating triple homozygotes.
- For single humanized PXR mouse: 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 Dispos 38(7): 1046-1053.
- For single humanized CAR mouse: 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.
- For the Humanized PXR-CAR-CYP3A4/3A7 Mouse: Hasegawa M, Kapelyukh Y, Tahara H, Seibler J, Rode A, Krueger S, Lee DN, Wolf CR, Scheer N (2011). Quantitative prediction of human pregnane X receptor and cytochrome P450 3A4 mediated drug-drug interaction in a novel multiple humanized mouse line. Mol Pharmacol 80(3):518-528.
- Ross J, Plummer SM, Rode A, Scheer N, Bower CC, Vogel O, Henderson CJ, Wolf CR, Elcombe CR. (2010). Human constitutive androstane receptor (CAR) and pregnane X receptor (PXR) support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogens phenobarbital and chlordane in vivo. Toxicol Sci. 116(2):452-466.