The Receptor Panel
Nuclear receptors play a major role in regulating the bodies’ response to chemical exposure.
The Pregnane X Receptor (PXR) and Constitutive Androstane Receptor (CAR) have the ability to bind a wide range of exogenous and endogenous ligands and, as a consequence, to control the level of expression of genes highly relevant to compound metabolism, such as the cytochrome P450s and drug transporters. Sequence variation in PXR and CAR between animals and man results in differences in the ability of exogenous ligands to interact and activate these transcription factors. Experimental data obtained in animal models, or in vitro test systems, may therefore not reflect the interactions which occur in man.
In order to circumvent this problem and to obtain a series of models in which the metabolic consequences of PXR and CAR activation by exogenous agents can be more accurately evaluated, we have created mouse models in which we have exchanged the corresponding murine genes for their human counterparts. Corresponding knockout models are also available. A publication describing these models can be found here.
Key utilities of these models include:
1. Demonstrating the relevance of rodent non-genotoxic carcinogenicity to man.
2. Dissecting mechanisms and consequences of human drug induction.
3. Improved Cytochrome P450 (CYP) induction screening.
Key advantages of these models include:
- Use of pure inbred C57Bl/6 genetic background. This will significantly aid reproducibility of results, as variance between mice will be minimised.
- Use of mouse promoters, and insertion of human genes into the corresponding mouse locus. Expression is therefore at endogenous levels and not restricted to the liver, but occurs in other organs where PXR and CAR are normally expressed.
- Use of large genomic inserts. This ensures the presence of all alternative human splice variants.
Availability
CXR and Taconic have partnered to make the transADMET™ Receptor models commercially available.
Contract services: CXR are co-exclusive suppliers of contract research services using transADMET™ mice. We also offer consultancy and advice to our customers. For more information on contract research services at CXR using the transADMET™ mice, contact us here or at transADMET@cxrbiosciences.com.
Off the shelf mice: Mice may be purchased directly from Taconic by both academic and for-profit customers. To purchase transADMET™ mice, please visit the relevant model webpages:
Publications
The Humanized PXR and CAR mouse models are described in the following publications:
Human constitutive androstane receptor (CAR) and pregnane X receptor (PXR) support the hypertrophic but not he hyperplastic response to the murine non-genotoxic hepatocarinogens phenobarbital and chlordane in vivo. ., Ross, J., Plummer, S., Rode, A., Scheer, N S., Vogel, O., Wolf, C.R., and Elcombe, C., (2010) epub J. Tox. Sci..
In vivo responses of the human and murine pregnane X receptor to dexamethasone in mice. Scheer N, Ross J, Kapelyukh Y, Rode A and Wolf CR, (2009) DMD on-line FASTFORWARD.
A Novel Panel of Mouse Models to Evaluate the Role of Human Pregnane X Receptor and Constitutive Androstane Receptor in Drug Response. Scheer N, Ross J, Rode A, Zevnik B, Niehaves S, Faust N, and Wolf CR ,(2008) JCI 118(9), pp3228–3239.
The HRN™ mouse.
A unique mouse model with no hepatic CYP450 activity, that can be used to determine ADME, PK and efficacy in the absence of confounding first-pass metabolism.
In vivo screening PK studies.
Small, cost effective PK studies, where multisampling techniques in mouse or rat mean compound and animal use is minimised.
Drug development solutions.
CXR combines proprietary technologies with improved application of traditional preclinical techniques and assays, including
in vitro and
in vivo ADME and Toxicology studies; cell culture; and an extensive analytical capability.
