The Cytochrome P450 Panel
Cytochrome P450-dependent monooxygenases (CYPs) are a group of enzymes that account for the Phase I metabolism of the majority of clinically used drugs. These enzymes have diverged significantly between species, both in their multiplicity and substrate specificity. This can result in altered drug metabolism profiles in animals and humans, leading to differences in the pharmacokinetics, efficacy and toxicity. The result: the outcomes of preclinical studies may not be predictive of the situation in man.
In response, we have derived and sourced a series of humanized and knockout CYP mouse models, which together make up the transADMETTM Cytochrome P450 Panel. We have focused on the key human enzymes accounting for the metabolism of the majority of marketed drugs.
Available Models The first models to be made available in the transADMETTM Cytochrome P450 panel are the CYP3A humanized and Cyp3a knockout mice. Additional models will follow.
A number of models are now available, allowing selection of the model best suited to your needs: For example, models where:
- CYP3A4 is constitutively expressed solely in the liver, at levels similar to those seen in average human liver, in order to investigate formation of human-specific metabolites (Humanized Liver CYP3A4 Mouse)
- CYP3A4 is under control of the human CYP3A4 promoter, resulting in more physiologically relevant levels of expression in both liver and intestine, allowing the effects of compounds on CYP3A4 regulation to be measured (Humanized CYP3A4/3A7 Mouse - this model also contains the foetally-expressed human CYP3A7, although this is not expressed in adult mice)
| | Taconic Model Number | Human CYP3A4/3A7
(human promoters) | ApoE promoter human CYP3A4 | Villin promoter human CYP3A4 | Knockout of 8 Cyp3a genes | Knockout of 7 Cyp3a genes | Genetic Background |
| Humanized CYP3A4/3A7 Mouse | 8842 |
X
| | | |
X |
C57BL/6 |
| Cyp3a(7gene) Knockout Mouse | 8841 | | | | |
X |
C57BL/6 |
| Humanized Liver CYP3A4 Mouse | 9048 | |
X | |
X | |
FVB |
| Humanized Gut CYP3A4 Mouse | 9047 | | |
X |
X | |
FVB |
| Humanized Liver & Gut CYP3A4 Mouse | 9049 | |
X |
X |
X | |
FVB |
| Cyp3a(8gene) Knockout Mouse* | 9011 | | | |
X | |
FVB |
* available as a Taconic Transgenic Model
CYP3A4 is the most abundant hepatic and intestinal CYP in humans and catalyzes the metabolism of over 50% of drugs in clinical use. There are many potential utilities of these models, including:
1. Studying human-specific metabolites in vivo.
2. Assessing the impact of gut vs. liver CYP3A4 metabolism on bioavailability.
3. Dissecting the contribution of the Cyp3a family to total bioavailability.
4. Examining the in vivo effects of CYP3A4 inhibition (for an example, see van Waterschoot RA et al. (2009) Inhibition and stimulation of intestinal and hepatic CYP3A activity: studies in humanized CYP3A4 transgenic mice using triazolam. DMD 37(12):2305-13.)
Availability
CXR and Taconic have partnered to make the transADMETTM Cytochrome P450 models commercially available.
Contract services: CXR are co-exclusive suppliers of contract research services using transADMETTM mice. We also offer consultancy and advice to our customers. For more information on contract research services at CXR using the transADMETTM 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 transADMETTM mice, please visit the relevant model webpages:
PublicationsThe Humanized Gut and Liver CYP3A4 mouse models are described in the following publications:
van Waterschoot RA et al. (2009) Inhibition and stimulation of intestinal and hepatic CYP3A activity: studies in humanized CYP3A4 transgenic mice using triazolam.
DMD 37(12):2305-13.
- Thummel (2007). Gut instincts: CYP3A4 and intestinal metabolism. JCI 117 (11):, p3173-3176.
- Herwaarden et al. (2007). Knockout of cytochrome P450 3A yields new mouse models for understanding xenobiotic metabolism. JCI 117 (11): 3583 – 3592.
Herwaarden et al. (2005). Midazolam and cyclosporin A metabolism in transgenic mice with liver-specific expression of human CYP3A4.
DMD 33 (7): 892 – 895.
The HRN™ mouse.
A unique mouse model with no hepatic CYP450 activity, that can be used to determine the effects of first-pass hepatic CYP 450 metabolism on the pharmacokinetics, efficacy and toxicity of compounds.
In vivo screening PK studies
Small, cost effective PK studies, where multisampling techniques in mouse mean compound and animal use is minimised.
