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PDZK1 regulates breast cancer resistance protein in small intestine

Takuya Shimizu1, Tomoko Sugiura, Tomohiko Wakayama

  • 1Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|August 6, 2011
PubMed

Insights

Transporter adaptor protein PDZK1 is crucial for apical localization of breast cancer resistance protein (BCRP) in the small intestine. This interaction regulates drug absorption and cellular resistance, impacting xenobiotic and nutrient transport.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Transporter adaptor protein PDZK1 influences xenobiotic and nutrient influx transporters in the small intestine.
  • PDZK1 deficiency in mice leads to reduced expression of transporters on the apical membrane.

Purpose of the Study:

  • To identify influx transporters responsible for cimetidine intestinal absorption using PDZK1-deficient mice.
  • To investigate the role of PDZK1 in the regulation and localization of breast cancer resistance protein (BCRP).

Main Methods:

  • Oral administration of cimetidine to wild-type and PDZK1 knockout mice.
  • Western blot and immunohistochemical analysis of intestinal brush-border membranes.
  • Cellular transport assays using Madin-Darby canine kidney II cells expressing BCRP and PDZK1.
  • Pull-down and immunoprecipitation assays to assess protein interactions.

Main Results:

  • PDZK1 knockout mice exhibited higher plasma cimetidine concentrations and altered pharmacokinetic profiles.
  • Reduced expression and apical localization of BCRP were observed in PDZK1-deficient mice.
  • Co-expression of PDZK1 and BCRP enhanced BCRP-mediated transport and cellular resistance to SN-38.
  • A physical interaction between PDZK1 and BCRP was confirmed.

Conclusions:

  • PDZK1 is essential for the apical localization of BCRP in the small intestine.
  • PDZK1 physically interacts with BCRP, regulating its membrane expression and function.
  • This study identifies PDZK1 as a novel regulator of BCRP in vivo.

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