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Involvement of Multidrug Resistance Associated Protein 1 (Mrp1) in the Efflux Transport of 17β Estradiol-D-17β-Glucuronide (E217βG) Across the Blood-Brain Barrier

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Abstract

Purpose.The purpose of present study is to investigate the involvement of multidrug resistance-associated protein 1 (Mrp1), Mrp2, and P-glycoprotein (Mdr1a) in the efflux transport of 17β—estradiol-D-17β-glucuronide (E217βG) across the blood—brain barrier (BBB).

Methods. 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]E217βG 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 E217βG 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 E217βG 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 E217βG by brain slices prepared from wild-type and Mrp1 knockout mice.

Conclusion. Mrp1, but not Mrp2, is involved in the excretion of E217βG at the BBB and provides a barrier function by extruding conjugated metabolites into the blood.

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Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Daisuke Sugiyama, Hiroyuki Kusuhara, Yong-Joo Lee & Yuichi Sugiyama

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  1. Daisuke Sugiyama
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  2. Hiroyuki Kusuhara
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  3. Yong-Joo Lee
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  4. Yuichi Sugiyama
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Correspondence to Yuichi Sugiyama.

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Sugiyama, D., Kusuhara, H., Lee, YJ. et al. Involvement of Multidrug Resistance Associated Protein 1 (Mrp1) in the Efflux Transport of 17β Estradiol-D-17β-Glucuronide (E217βG) Across the Blood-Brain Barrier. Pharm Res 20, 1394–1400 (2003). https://doi.org/10.1023/A:1025749925541

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