This model carries disruptions or deletions of all eight full-length mouse Cyp3a genes identified
Contains two targeted regions, a single gene knockout of the Cyp3a13 gene, and a cre-mediated deletion of the following gene cluster: Cyp3a11, Cyp3a16, Cyp3a25, Cyp3a41, Cyp3a44, Cyp3a57, Cyp3a58-ps, Cyp3a59
In humans, CYP3A enzymes metabolize most drugs
Intestinal expression of CYP3A enzymes in humans can cause significant intestinal metabolism of compounds, resulting in impaired drug absorption
This model may be used in combination with other models which express human CYP3A4 in either the gut (9047) or the liver (9048) to determine the contribution of intestinal metabolism to the absorption and distribution of a test article
Genetic Background: FVB Background
Origin: The Cyp3a Knockout model was developed by Alfred Schinkel at the Netherlands Cancer Institute. The model was generated by targeting of the Cyp3a13 gene in 129P2/OlaHsd-derived E14 ES cells to replace the putative promoter region and exons 1 and 2 with a Pgk-hygromycin cassette. Targeted ES cells were injected into blastocysts. Resultant chimeras were backcrossed to FVB/N for at least seven generations. To generate the cluster deletion, the intronic sequence between exon 2 and 3 of Cyp3a57 was replaced with a neo cassette containing a loxP site, and a hygromycin cassette with a loxP site was inserted downstream of the Cyp3a59 gene in 129P2/OlaHsd-derived E14 ES cells through gene targeting. Transfection of the ES cells with cre recombinase resulted in the deletion of Cyp3a57, Cyp3a16, Cyp3a41, Cyp3a44, Cyp3a11, Cyp3a25 and Cyp3a59. The targeted ES cells were injected into blastocysts. Resultant chimeras were backcrossed two generations to FVB/N. Mice with the cluster deletion were then backcrossed to the Cyp3a13 targeted mutation line for at least six generations to generate a model with disruption or deletion of all eight full-length mouse Cyp3a genes. Taconic received stock in 2008, and the line was embryo transfer derived by mating male and female mice homozygous for both targeted regions. The line was maintained by mating male and females homozygous for the Cyp3a13 disruption and the cluster deletion.
van Herwaarden AE, Wagenaar E, van der Kruijssen CM, van Waterschoot RA, Smit JW, Song JY, van der Valk MA, van Tellingen O, van der Hoorn JW, Rosing H, Beijnen JH, Schinkel AH. (2007) Knockout of cytochrome P450 3A yields new mouse models for understanding xenobiotic metabolism. J Clin Invest 117(11):3583-92