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Multidrug resistance protein 4 (MRP4/ABCC4) mediates efflux of bimane-glutathione

Jing Bai1, Liqi Lai, Hui Ching Yeo

  • 1Department of Biochemistry, Faculty of Medicine, National University of Singapore, MD7, 8 Medical Drive, S117597, Singapore, Singapore.

The International Journal of Biochemistry & Cell Biology
|December 4, 2003
PubMed

Insights

The ATP-dependent export pump ABCC4 (MRP4) transports glutathione conjugates, suggesting a role in cellular detoxification. This finding expands our understanding of multidrug resistance protein functions.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Multidrug resistance proteins (MRPs) are ATP-dependent efflux pumps involved in transporting organic anions.
  • ABCC1-3 (MRP1-3) transport various anionic conjugates, including glutathione, glucuronide, and sulfate conjugates.
  • ABCC4 (MRP4) was previously known to transport cyclic nucleotides and estradiol-17-beta-D-glucuronide, but its substrate specificity for other conjugates was unclear.

Purpose of the Study:

  • To investigate whether ABCC4 (MRP4) can transport other conjugated metabolites, specifically glutathione conjugates.
  • To characterize the transport activity of ABCC4 using a fluorescent glutathione conjugate substrate.

Main Methods:

  • Utilized cells stably overexpressing ABCC4 (MRP4).
  • Employed a fluorescent substrate, bimane-glutathione (bimane-GS), to assess ABCC4-mediated efflux.
  • Investigated the effect of known MRP inhibitors (carbonylcyanide m-chlorophenylhydrasone, benzbromarone, verapamil, indomethacin), ABCC4 substrates (methotrexate), and a substrate precursor (6-thioguanine) on bimane-GS efflux.
  • Examined the inhibitory effect of 1-chloro-2,4-dinitrobenzene (CDNB), a precursor to a glutathione conjugate, on bimane-GS efflux.

Main Results:

  • ABCC4 (MRP4) demonstrated facilitation of bimane-glutathione efflux, with over 85% exported within 15 minutes.
  • This transport was inhibited by carbonylcyanide m-chlorophenylhydrasone, benzbromarone, verapamil, and indomethacin.
  • Efflux was reduced by known ABCC4 substrates/precursors like methotrexate and 6-thioguanine, and inhibited by CDNB in a concentration-dependent manner.

Conclusions:

  • ABCC4 (MRP4) actively transports glutathione conjugates, expanding its known substrate repertoire.
  • The findings suggest that ABCC4 (MRP4) plays a significant role in the cellular efflux of Phase II detoxification metabolites, including glutathione and potentially glucuronide conjugates.
  • This implicates ABCC4 (MRP4) in cellular defense mechanisms against xenobiotics and endogenous compounds.

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