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.