Characterization of 5(6)-carboxy-2,'7'-dichlorofluorescein transport by MRP2 and utilization of this substrate as a fluorescent surrogate for LTC4

J Biomol Screen. 2008 Apr;13(4):295-301. doi: 10.1177/1087057108316702. Epub 2008 Mar 18.

Abstract

MRP2 (ABCC2) is an efflux transporter expressed on the apical membrane of polarized cells. This protein has a major role in the biliary elimination of toxic compounds from the liver. As MRP2 transports many endogenous compounds, including LTC4 as well as xenobiotics and toxic phase II metabolites, blockade of this transporter may cause the accumulation of these compounds in the hepatocyte, resulting in hepatotoxicity. The vesicular transport assay is a great tool to study drug-drug and drug-endogenous compound interactions of ABC transporters. In this assay, inside-out membrane vesicles are used, so the test compound can readily access the transporter. As MRP2 transports many ionic compounds that are difficult to investigate in a whole-cell system because of permeability reasons, the vesicular transport assay is a good choice for screening MRP2-mediated interactions. LTC4 is not an optimal substrate for high-throughput screening for MRP2 interactors, even though it is an important MRP2 substrate. Therefore, the transport of a drug surrogate, 5(6)-carboxy-2,'7'-dichlorofluorescein (CDCF), by MRP2 was characterized using the vesicular transport assay. The data indicate that CDCF proves to be an ideal substrate for MRP2 vesicular transport assay with its optimal detection and transport properties.

MeSH terms

  • Biological Transport
  • Fluoresceins / metabolism*
  • Fluorescent Dyes / metabolism*
  • Humans
  • Kinetics
  • Leukotriene C4 / metabolism*
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Reproducibility of Results

Substances

  • ABCC2 protein, human
  • Fluoresceins
  • Fluorescent Dyes
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins
  • 5(6)-carboxy-2',7'-dichlorofluorescein
  • Leukotriene C4