Transport of Fluorescein in MDCKII-MRP1 Transfected Cells and mrp1-Knockout Mice

doi:10.1006/bbrc.2001.5062

Biochemical and Biophysical Research Communications

Volume 284, Issue 4, 22 June 2001, Pages 863-869

https://doi.org/10.1006/bbrc.2001.5062 Get rights and content

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.

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^☆: This 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.

²: To whom correspondence should be addressed. Fax: 402-559-9543. E-mail: [email protected].

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Regular ArticleTransport of Fluorescein in MDCKII-MRP1 Transfected Cells and mrp1-Knockout Mice☆

Abstract

Bioorg. Med. Chem. Lett.

Brain Res.

Biochem. Biophys. Res. Commun.

J. Cont. Release.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

Cell

Brain Res.

Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line

Science

Expression pattern of MRP in human tissues and adult solid tumor cell lines

J. Natl. Cancer Inst.

Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes

Drug Metab. Dispos.

Pluronic P85 enhances the delivery of digoxin to the brain: In vitro and in vivo studies

J. Pharmacol. Exp. Therap.

Mrp1 multidrug resistance-associated protein and P-glycoprotein expression in rat brain microvessel endothelial cells

J. Neurochem.

Characterization of efflux transport of organic anions in a mouse brain capillary endothelial cell line

J. Pharmacol. Exp. Ther.

Functional expression of P-glycoprotein and multidrug resistance-associated protein (Mrp1) in primary cultures of rat astrocytes

J. Neurosci. Res.

Modulation of multidrug resistance protein expression in porcine brain capillary endothelial cells in vitro

Drug Metab. Disposit.

Regular Article
Transport of Fluorescein in MDCKII-MRP1 Transfected Cells and mrp1-Knockout Mice☆