A novel panel of mouse models to evaluate the role of human pregnane X receptor and constitutive androstane receptor in drug response
| Autor: | Nicole Faust, Anja Rode, Branko Zevnik, Jillian Ross, Sandra Niehaves, Nico Scheer, C. Roland Wolf |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Receptors
Steroid Chemistry Pharmaceutical Drug Evaluation Preclinical Receptors Cytoplasmic and Nuclear Pharmacology Models Biological digestive system Mice In vivo Constitutive androstane receptor Animals Humans RNA Messenger Receptor Transcription factor Alleles Constitutive Androstane Receptor P-glycoprotein Mice Knockout Pregnane X receptor Models Genetic biology Pregnane X Receptor General Medicine Ligand (biochemistry) digestive system diseases Cell biology Genetic Techniques Technical Advance Nuclear receptor Models Animal biology.protein human activities Transcription Factors |
| Zdroj: | Journal of Clinical Investigation. 118:3228-3239 |
| ISSN: | 0021-9738 |
| Popis: | The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are closely related orphan nuclear hormone receptors that play a critical role as xenobiotic sensors in mammals. Both receptors regulate the expression of genes involved in the biotransformation of chemicals in a ligand-dependent manner. As the ligand specificity of PXR and CAR have diverged between species, the prediction of in vivo PXR and CAR interactions with a drug are difficult to extrapolate from animals to humans. We report the development of what we believe are novel PXR- and CAR-humanized mice, generated using a knockin strategy, and Pxr- and Car-KO mice as well as a panel of mice including all possible combinations of these genetic alterations. The expression of human CAR and PXR was in the predicted tissues at physiological levels, and splice variants of both human receptors were expressed. The panel of mice will allow the dissection of the crosstalk between PXR and CAR in the response to different drugs. To demonstrate the utility of this panel of mice, we used the mice to show that the in vivo induction of Cyp3a11 and Cyp2b10 by phenobarbital was only mediated by CAR, although this compound is described as a PXR and CAR activator in vitro. This panel of mouse models is a useful tool to evaluate the roles of CAR and PXR in drug bioavailability, toxicity, and efficacy in humans. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|