The HRN™ Mouse
The Hepatic Reductase Null (HRN™ ) mouse lacks cytochrome P450 activity in the liver and thus provides an elegant tool for determining the role of hepatic P450 metabolism in drug disposition in vivo.
Typical applications of the HRN™ mouse at CXR include:
- Evaluation of the role of hepatic cytochrome P450 metabolism in drug bioavailability. The role of extrahepatic metabolism can also be assessed using the cytochrome P450 inhibitor ABT.
- Demonstration of in vivo drug efficacy by eliminating the major confounding factor of hepatic cytochrome P450-mediated metabolism.
- Evaluation of the contribution of metabolites to efficacy or toxicity
The HRN™ Nude
CXR can carry out xenograft studies on the HRN™ Nude mouse, thereby allowing an evaluation of in vivo efficacy without confounding first-pass metabolism.
Availability
The HRN™ mouse is routinely used in ADME & Toxicity evaluations as part of CXR Biosciences service offering. The usefulness of the HRN™ can be evaluated at CXR on a fee for service basis. Alternatively breeding pairs of HRN™ mice can be supplied to establish an in house colony under licence. CXR has also entered into a marketing agreement with Taconic Farms Inc. to supply HRN as part of Taconic portfolio of transgenic mice.
For further information download the The HRN™ mouse brochure here
Download pdf
Below are a few key publications demontrasting the use of the HRN™ mouse -
- 'The hepatic reductase null mouse as a model for exploring hepatic conjugation of xenobiotics: Application to the metabolism of diclofenac.' Kathryn Pickup, Alex Gavin, Huw B Jones, Elin Karlsson, Chris Page, Kerry Ratcliffe, Sunil Sarda, Timothy Schulz-Utermoehl, and Ian Wilson. Xenobiotica, 2012 Feb;42(2):195-205
- Genentech poster demonstrating use of the HRN™ mouse, with and without the CYP450 inhibitor ABT, to determine effects of hepatic vs. extrahepatic CYP 450 metabolism on bioavailability. The poster was presented at ISSX 2009.
-‘Relationship between hepatic phenotype and changes in gene expression in the cytochrome P450 reductase (POR) null mice.’ Wang, X.J., Chamberlain, M., Vassieva, O., Henderson, C.J. and Wolf,C.R. Biochem. J. (2005) 388, 857-867.
- ‘Role of hepatic cytochrome P450s in the pharmacokinetics and toxicity of cyclophosphamide: Studies using the hepatic cytochrome P450 reductase null mouse’. Pass, G.J., Carrie, D., Boylan, M.,Lorimore, S., Wright, E., Houston, B., Henderson C.J. and Wolf. C.R. Cancer Res. (2005) 65, 4211-4217.
- ‘Inactivation of the hepatic cytochrome P450 system by conditional deletion of hepatic cytochrome P450 reductase’.
Henderson, C.J., Otto, D.M., Carrie, D., Magnuson, M.A., McLaren, A.W., Rosewell, I. and Wolf, C.R. J. Biol. Chem. (2003) 278:13480-13486.
In vivo screening PK studies.
Small, cost effective PK studies, where multisampling techniques in mouse or rat mean compound and animal use is minimised.
transADMET™ mice.
Key murine genes involved in the metabolic response to drugs (e.g. PXR, CAR, cytochrome P450s, drug transporters) are replaced with their human equivalents to give a more predictive and “human-like” response.
