Modeling Human Cytochrome P450 2D6 Metabolism and Drug-Drug Interaction by a Novel Panel of Knockout and Humanized Mouse Lines (original) (raw)
Research ArticleArticle
, Yury Kapelyukh, Jillian McEwan, Vincent Beuger, Lesley A. Stanley, Anja Rode and C. Roland Wolf
Molecular Pharmacology January 2012, 81 (1) 63-72; DOI: https://doi.org/10.1124/mol.111.075192
Abstract
The highly polymorphic human cytochrome P450 2D6 enzyme is involved in the metabolism of up to 25% of all marketed drugs and accounts for significant individual differences in response to CYP2D6 substrates. Because of the differences in the multiplicity and substrate specificity of CYP2D family members among species, it is difficult to predict pathways of human CYP2D6-dependent drug metabolism on the basis of animal studies. To create animal models that reflect the human situation more closely and that allow an in vivo assessment of the consequences of differential CYP2D6 drug metabolism, we have developed a novel straightforward approach to delete the entire murine Cyp2d gene cluster and replace it with allelic variants of human CYP2D6. By using this approach, we have generated mouse lines expressing the two frequent human protein isoforms CYP2D6.1 and CYP2D6.2 and an as yet undescribed variant of this enzyme, as well as a Cyp2d cluster knockout mouse. We demonstrate that the various transgenic mouse lines cover a wide spectrum of different human CYP2D6 metabolizer phenotypes. The novel humanization strategy described here provides a robust approach for the expression of different CYP2D6 allelic variants in transgenic mice and thus can help to evaluate potential CYP2D6-dependent interindividual differences in drug response in the context of personalized medicine.
Footnotes
↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This work was supported in part by ITI Life Sciences, Scotland.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
http://dx.doi.org/10.1124/mol.111.075192.ABBREVIATIONS:
WT
wild-type
kb
kilobase(s)
ES
embryonic stem
KO
knockout
HLM
human liver microsomes
AUC
area under the concentration-time curve
MR
metabolic ratio.Received August 12, 2011.
Accepted October 11, 2011.
Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
Log in using your username and password
Purchase access
You may purchase access to this article. This will require you to create an account if you don't already have one.