PT  - JOURNAL ARTICLE
AU  - Shannon Dallas
AU  - Laurent Salphati
AU  - David Gomez-Zepeda
AU  - Thomas Wanek
AU  - Liangfu Chen
AU  - Xiaoyan Chu
AU  - Jeevan Kunta
AU  - Mario Mezler
AU  - Marie-Claude Menet
AU  - Stephanie Chasseigneaux
AU  - Xavier Decleves
AU  - Oliver Langer
AU  - Esaie Pierre
AU  - Karen DiLoreto
AU  - Carolin Hoft
AU  - Loic Laplanche
AU  - Jodie Pang
AU  - Tony Pereira
AU  - Clara Andonian
AU  - Damir Simic
AU  - Anja Rode
AU  - Jocelyn Yabut
AU  - Xiaolin Zhang
AU  - Nico Scheer
TI  - Generation and Characterization of a Breast Cancer Resistance Protein Humanized Mouse Model
AID  - 10.1124/mol.115.102079
DP  - 2016 Jan 01
TA  - Molecular Pharmacology
PG  - mol.115.102079
4099  - http://molpharm.aspetjournals.org/content/early/2016/02/18/mol.115.102079.short
4100  - http://molpharm.aspetjournals.org/content/early/2016/02/18/mol.115.102079.full
AB  - The breast cancer resistance protein (BCRP) is expressed in various tissues, such as the gut, liver, kidney and blood brain barrier (BBB), where it mediates the unidirectional transport of substrates to the apical/luminal side of polarized cells. Thereby BCRP acts as an efflux pump, mediating the elimination or restricting the entry of endogenous compounds or xenobiotics into tissues and it plays important roles in drug disposition, efficacy and safety. Bcrp knockout mice (Bcrp-/-) have been used widely to study the role of this transporter in limiting intestinal absorption and brain penetration of substrate compounds. Here we describe the first generation and characterization of a mouse line humanized for BCRP (hBCRP), in which the mouse coding sequence from the start to stop codon was replaced with the corresponding human genomic region, such that the human transporter is expressed under control of the murine Bcrp promoter. We demonstrate robust human and loss of mouse BCRP/Bcrp mRNA and protein expression in the hBCRP mice and the absence of major compensatory changes in the expression of other genes involved in drug metabolism and disposition. Pharmacokinetic and brain distribution studies with several BCRP probe substrates confirmed the functional activity of the human transporter in these mice. Furthermore, we provide practical examples for the use of hBCRP mice to study drug-drug interactions (DDIs). The hBCRP mouse is a promising model to study the in vivo role of human BCRP in limiting absorption and BBB penetration of substrate compounds and to investigate clinically relevant DDIs involving BCRP.