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This targeted mutation strain carries a replacement of the nine functional mouse Cyp2d genes (Cyp2d22, Cyp2d11, Cyp2d10, Cyp2d9, Cyp2d12, Cyp2d34, Cyp2d13, Cyp2d40, Cyp2d26) with approximately 13 kb of genomic human DNA comprising CYP2D6.
CYP2D6 catalyzes the metabolism of more than 20% of drugs in clinical use and is highly polymorphic in humans.
May be used as a bioreactor to generate human-specific metabolites, to determine the relevance of CYP2D6 in drug metabolism or for CYP2D6 inhibition studies.
May be used with 9178, which is knocked out for the mouse Cyp2d cluster, to predict the differences in response of human poor and extensive CYP2D6 metabolisers.
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Genetic Background: C57BL/6 Background
The Humanized CYP2D6 Mouse was developed by Taconic in collaboration with CXR Biosciences. It was created by first replacing mouse exon 1 to 4 of Cyp2d26 with a hygromycin cassette containing both loxP and frt sites and subsequently replacing mouse exons 4 and 5 of Cyp2d22 with a genomic human CYP2D6 expression cassette containing additional loxP and frt sites through gene targeting in C57BL/6NTac-derived ES cells. The targeted ES cells were injected into BALB/cJBomTac blastocysts and the resultant chimeras were backcrossed to a Cre deleter strain on C57BL/6J to delete the mouse Cyp2d cluster, while retaining the human CYP2D6 expression cassette. The colony is maintained by mating homozygotes.
Scheer et al. (2012) Modeling Human Cytochrome P450 2D6 Metabolism and Drug-Drug Interaction by a Novel Panel of Knockout and Humanized Mouse Lines. Mol Pharmacol. (2012) Jan;81(1):63-72.