Generation and Characterization of a Breast Cancer Resistance Protein Humanized Mouse Model.

Molecular Pharmacology
Shannon DallasNico Scheer

Abstract

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 murineBcrppromoter. 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 con...Continue Reading

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Citations

Sep 18, 2016·Advanced Drug Delivery Reviews·Yan LiJames W Paxton
Jun 27, 2018·Expert Opinion on Drug Discovery·Donna A Volpe, Hisham Qosa
Aug 30, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yamato SanoHiroyuki Kusuhara
Nov 7, 2020·International Journal of Molecular Sciences·Thomas WanekOliver Langer
Jun 2, 2021·Chemico-biological Interactions·Esther Blanco-PaniaguaGracia Merino

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