ORIGIN
At the Hubrecht Institute a nonsense mutation at amino acid position 59 (Glu to stop) within the catalytic center ABC transporter-like domain of the rat Abcg2 (Bcrp) gene was isolated which eliminates all wild-type protein. Transferred to Charles River under exclusive license from Transposagen in 2010.
STRAIN CODE
496 (HOMOZYGOUS)
497 (HETEROZYGOUS)
498 (WILD-TYPE)
COAT COLOR
White (albino)
MODEL INFORMATION
The Abcg2 (Bcrp) TGEM® Rat Model harbors a premature stop codon (nonsense mutation at amino acid position E59 in the ABC transporter-like domain). Due to the rat’s close physiological similarities to humans, this model will improve in vivo ADME-tox and pharmacokinetics studies. The in vivo drug transport studies that are conducted in the Abcg2 (Bcrp) TGEM® Rat Model will enhance the ability to predict how drug candidates will perform in humans. These studies are critical for therapeutic development and usually required by the FDA for approval to conduct human clinical trials.
Abcg2 (Bcrp) is known to regulate the bioavailability of the following substances:
- Chemotherapy agents such as Gleevec, mitoxantrone, doxorubicin, tyrosine kinase inhibitors and topoisomerase inhibitors
- Dietary and environmental xenotoxins such as aflatoxin
- Hepatocarcinogens
- Riboflavin
- Diuretic drugs
- Heme/Porphyrins
- Antiulcer drugs such as cimetidine
The expression of Abcg2 (Bcrp) tightly regulates the fate and function of subpopulations (SP) of cells with stem or progenitor properties in various tissues, including cardiac, tumor initiating cells (cancer stem cells), hematopoietic stem cells, bone marrow, gonad, lung, skeletal muscle and retinal cells(1). Therefore, the Abcg2 (Bcrp) TGEM® Rat Model may be useful for in vivo stem cell therapeutic studies. The model also provides a great assay to determine stem cell replacement therapy pro-proliferative or pro-differentiation properties, especially during tissue injury when proliferation is necessary. Testing new therapies such as stem cells in rat models has advantages for drug development and regulatory approval. Therefore, the Abcg2 (Bcrp) TGEM® Rat Model is suitable as an ideal tool for stem cell therapy development.
Humans and animal models with low or deficient Abcg2 (Bcrp) expression develop extreme sensitivity to dietary chlorophyll-breakdown product phenophorbide-a, resulting in phototoxic lesions on light exposed skin. The Abcg2 (Bcrp) TGEM® Rat Model may be a useful model for studying protoporphyria and diet-induced phototoxicity(2).
The Abcg2 (Bcrp) TGEM® Rat Model is deficient for a regulator of hypoxia. Abcg2 (Bcrp) binds and transports heme. In hematopoietic cells, Abcg2 (Bcrp) regulates sensitivity to heme accumulation and hypoxia, which can lead to mitrochondrial failure and cell death. Abcg2 (Bcrp) is upregulated during hypoxia, reduces heme accumulation to reduce hypoxic demand(3).
References
1) Pfister et al. (2008) Circ. Res. 103 (8): 825-35
2) Jonker et al. (2002) PNAS. 99 (24): 15649-54
3) Krishnamurthy et al. (2004) J. Biol. Chem. 279: 24218-225
RESEARCH APPLICATION
ADME, drug transport, toxicology, pharmacokinetics, bioavailability, blood-brain barrier transport, stem cells, progenitor cells, proliferation, differentiation, tumor initiating cells, phototoxicity, protoporphyria, hypoxia
ORDERING INFORMATION
Please call 1.800.LAB.RATS if you would like to place an order.
For additional information about the Bcrp TGEM® rats, please contact us at 1.877.CRIVER.1 or askcharlesriver@crl.com.