Involvement of multidrug resistance associated protein 1 (Mrp1) in the efflux transport of 17beta estradiol-D-17beta-glucuronide (E217betaG) across the blood-brain barrier

Pharm Res. 2003 Sep;20(9):1394-400. doi: 10.1023/a:1025749925541.


Purpose: The purpose of present study is to investigate the involve ment of multidrug resistance-associated protein 1 (Mrp1), Mrp2, an P-glycoprotein (Mdr1a) in the efflux transport of 17beta-estradiol-D-17beta-glucuronide (E217betaG) across the blood-brain barrier (BBB).

Method: The expression of Mrp1 and Mrp2 at the BBB was investigated by RT-PCR and Western blot analyses. The time profiles of the remaining radioactivity of [3H]E217pG in the brain were compared in wild-type, Mdr1a/Mdr1b and Mrp1 knockout mice and normal and Mrp2-deficient mutant rats [Sprague-Dawley and Eisai hyperbilirubinemic rats (EHBR), respectively] after intracerebral microinjection.

Results: RT-PCR and Western blot analyses revealed the expression of Mrp1 in isolated rat brain capillary; however, RT-PCR was unable to detect any expression of Mrp2. Significant elimination of E217betaG was observed in wild-type mice at a rate constant of 0.007 min(-1) which was significantly decreased (0.004 min(-1)) in Mrp1 knockout mice. In contrast, there was no difference in the efflux of E217betaG from the brain in wild-type and Mdr1a/Mdr1b knockout mice and in normal and EHBR. No significant difference was observed in the accumulation of E217betaG by brain slices prepared from wild-type and Mrp1 knockout mice.

Conclusion: Mrp1, but not Mrp2, is involved in the excretion of E217betaG at the BBB and provides a barrier function by extruding conjugated metabolites into the blood.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP-Binding Cassette Transporters*
  • Animals
  • Blood-Brain Barrier / metabolism*
  • Blotting, Western
  • Brain / blood supply
  • Brain / metabolism
  • Capillaries / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Chromatography, High Pressure Liquid
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacokinetics*
  • Male
  • Mice
  • Mice, Knockout
  • Microinjections
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • Species Specificity
  • Time Factors


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Abcc2 protein, rat
  • Carrier Proteins
  • Multidrug Resistance-Associated Proteins
  • estradiol-17 beta-glucuronide
  • Estradiol
  • multidrug resistance-associated protein 1