Transport of fluorescein in MDCKII-MRP1 transfected cells and mrpl-knockout mice

Haiying Sun, Dennis R. Johnson, Rick A. Finch, Alan C. Sartorelli, Donald W. Miller, William F. Elmquist

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

The multidrug resistant-associated protein 1 (MRP1) is a membrane-bound transport protein that is involved in the efflux of organic anions and has been implicated in multidrug resistance in cancer. MRP1 has also been reported to be ubiquitously expressed in normal tissues, including the brain. The presence of functional organic anion transporters in the blood-brain and blood-CSF barriers that influence the distribution of various compounds to the brain has long been known. The purpose of this study was to examine the role of MRP1 in the brain distribution of a model organic anion, fluorescein. The substrate specificity of MRP1 for fluorescein was initially determined by examining the accumulation of fluorescein in MDCKII MRP1-transfected cells. The distribution of fluorescein in the brain was then examined in wild-type and mrp1 gene knockout mice. The results show that in MDCKII MRP1-transfected cells, the accumulation of fluorescein was significantly lower (about 40% lower) than that in wild-type MDCKII cells. MRP1 inhibitors such as probenecid, MK-571, and LY402913 enhanced fluorescein accumulation in MDCKII MRP1-transfected cells to a greater extent than in wild-type MDCKII cells. In an in vivo study, after intravenous injection of fluorescein, the fluorescein brain-to-plasma concentration ratio in mrp1 knockout mice was not significantly different than that in wild-type mice. However, when probenecid was co-administered with fluorescein in wild-type mice, the fluorescein brain-to-plasma ratio was significantly increased (1.5-fold). These findings suggest that fluorescein is a substrate for MRP1. Furthermore, the in vivo study also suggests that MRP1 has a limited role in the transport and distribution of fluorescein in the brain. Therefore, other organic anion transport proteins, including the various isoforms of the MRP family, may be responsible for the accumulation and transport of organic anions in the brain.

Original languageEnglish (US)
Pages (from-to)863-869
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume284
Issue number4
DOIs
StatePublished - 2001

Bibliographical note

Funding Information:
1This research was supported in part by U.S. Public Health Service Grants from the National Cancer Institute, CA-75466 (W.F.E.), from the National Institute of Child Health and Human Development, HD/DA-3997 (A.C.S.), and Grants from the Nebraska Research Initiative Drug Delivery Program. Ms. Sun was supported by Graduate Fellowships from the University of Nebraska Medical Center and a Presidential Fellowship awarded by the University of Nebraska.

Keywords

  • Blood-brain barrier
  • Brain transport
  • Drug efflux proteins
  • Fluorescein
  • MDCKII cells
  • MRP1
  • Mrp1-knockout mice
  • Multidrug resistance

Fingerprint

Dive into the research topics of 'Transport of fluorescein in MDCKII-MRP1 transfected cells and mrpl-knockout mice'. Together they form a unique fingerprint.

Cite this