RT Journal Article
SR Electronic
T1 Generation and Characterization of a Breast Cancer Resistance Protein Humanized Mouse Model
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 492
OP 504
DO 10.1124/mol.115.102079
VO 89
IS 5
A1 Dallas, Shannon
A1 Salphati, Laurent
A1 Gomez-Zepeda, David
A1 Wanek, Thomas
A1 Chen, Liangfu
A1 Chu, Xiaoyan
A1 Kunta, Jeevan
A1 Mezler, Mario
A1 Menet, Marie-Claude
A1 Chasseigneaux, Stephanie
A1 Declèves, Xavier
A1 Langer, Oliver
A1 Pierre, Esaie
A1 DiLoreto, Karen
A1 Hoft, Carolin
A1 Laplanche, Loic
A1 Pang, Jodie
A1 Pereira, Tony
A1 Andonian, Clara
A1 Simic, Damir
A1 Rode, Anja
A1 Yabut, Jocelyn
A1 Zhang, Xiaolin
A1 Scheer, Nico
YR 2016
UL http://molpharm.aspetjournals.org/content/89/5/492.abstract
AB 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.