Abstract
ATP-binding cassette transporters such as ABCB1 (P-gp), ABCC1 (MRP1) and ABCG2 (BCRP) are well known for their role in rendering cancer cells resistant to chemotherapy. Additionally, more recent research provided evidence that, along with other ABC transporters (ABCA1, ABCA7), they might be cornerstones to tackle neurodegenerative diseases. Overcoming chemoresistance in cancer, understanding drug-drug interactions and developing efficient and specific drugs that alter ABC transporter function are hindered by a lack of in vivo research models which are fully predictive for humans. Hence, the humanization of ABC transporters in mice has become a major focus in pharmaceutical and neurodegenerative research. Here, we present a characterization of the first Abcc1 humanized mouse line. In order to preserve endogenous expression profiles, we chose to generate a knock-in that leads to the expression of a chimeric protein that is fully human except for one amino acid. We found robust mRNA and protein expression within all major organs analyzed (brain, lung, spleen and kidney). Furthermore, we demonstrate the functionality of the expressed human ABCC1 protein in brain and lungs using functional positron emission tomography (PET) imaging in vivo. Through the introduction of loxP sites, we additionally enabled this humanized mouse model for highly sophisticated studies involving cell-type specific transporter ablation. Based on our data, the presented mouse model appears as a promising model for the investigation of cell-specific ABCC1 functions and should provide a basis for better translation of pre-clinical research.
SIGNIFICANCE STATEMENT Humanised ABCC1 transporter mice can be used in different fields of reearch: cancer, epilepsy, neurodegenerative diseases, drug discovery.
- ABC transporters
- Blood-brain barrier
- Dementia
- Drug transport
- Endothelial cells
- Multidrug resistance protein (MRP)
- The American Society for Pharmacology and Experimental Therapeutics