Require in vivo evidence that liver tumours seen in your tox study aren’t relevant to man?
The problem
Liver carcinogencity is a relatively common finding in long-term rodent carcinogenicity studies. Indeed, many marketed chemicals and drugs (including some benzodiazepines, barbiturates and fibrates) are known to be rodent non-genotoxic liver carcinogens.
When liver carcinogenicity is observed in rodent studies, the challenge is to demonstrate whether this finding is relevant to man in a mechanistic, rapid and cost-effective way.
The solution
The nuclear receptors Constitutive Androstane Receptor (CAR) and Pregnane X Receptor (PXR) regulate metabolism in a species-specific manner in response to xenobiotics. It is known that long-term treatments with PXR and CAR activators can cause liver tumours in rodents, possibly due to their ability to increase cell proliferation and suppress apoptosis. Available data suggests that human PXR and CAR do not support this carcinogenic effect.
The clinically used drug phenobarbital and the pesticide chlordane are both rodent non-genotoxic liver carcinogens. CXR Biosciences has used double humanised PXR/CAR receptor mice (termed the Humanized PXR-CAR Mouse) to demonstrate that the human receptors do not support the proliferative effects seen in wild type mice.
The Humanized PXR-CAR Mouse model can therefore be used to mechanistically demonstrate human relevance of rodent liver carcinogenesis.
Study design
Results
The nuclear incorporation of BrdU was determined as a measure of cell proliferation:
- In wild-type mice, phenobarbital and chlordane treatment increased hepatocellular proliferation labelling index (S-phase) by approximately 7-fold and 11-fold, respectively.
- However, no change in S-phase was detected in either the Humanized PXR-CAR Mouse model or the Pxr-Car Knockout Mouse model following chlordane or phenobarbital treatment:
Figure 1: WT = C57BL; hPXR/hCAR = Humanized PXR-CAR Mouse; PXRKO/CARKO = Pxr-Car Knockout Mouse.
Using these novel models, we have shown that it is unlikely that exposure to chlordane and phenobarbital poses a hepatocarcinogenic hazard to humans. Further data is available on request from CXR Biosciences.
These observations support the utility of these humanised models in demonstrating lack of relevance to man.
On September 14th 2009, it was announced at EUROTOX 2009 that the humanised and knockout CAR mice will play an integral part in the proposed European Commission Innovative Medicines Initiative (IMI) program to investigate non-genotoxic carcinogenicity.
Availability
CXR and Taconic have partnered to make the transADMET™ Pxr-Car Knockout Mouse model and Humanized PXR-CAR Mouse model 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 and have many years of experience assessing the human-relevance of non-genotoxic carcinogenicity.
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:
For questions regarding distribution of these models, please contact Dr. Megan MacBride.
Reference
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..
