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Research ArticleArticle

In Vivo Imaging of Human MDR1 Transcription in the Brain and Spine of MDR1-Luciferase Reporter Mice

Kazuto Yasuda, Cynthia Cline, Yvonne S. Lin, Rachel Scheib, Samit Ganguly, Ranjit K. Thirumaran, Amarjit Chaudhry, Richard B. Kim and Erin G. Schuetz
Drug Metabolism and Disposition November 2015, 43 (11) 1646-1654; DOI: https://doi.org/10.1124/dmd.115.065078
Kazuto Yasuda
Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee (K.Y., C.C., R.S., S.G., R.K.T., A.C., E.G.S.); Department of Medicine, Division of Clinical Pharmacology, University of Western Ontario, London, Ontario, Canada (R.B.K.); and Department of Pharmaceutics, The University of Washington, Seattle, Washington (Y.S.L.)
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Cynthia Cline
Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee (K.Y., C.C., R.S., S.G., R.K.T., A.C., E.G.S.); Department of Medicine, Division of Clinical Pharmacology, University of Western Ontario, London, Ontario, Canada (R.B.K.); and Department of Pharmaceutics, The University of Washington, Seattle, Washington (Y.S.L.)
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Yvonne S. Lin
Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee (K.Y., C.C., R.S., S.G., R.K.T., A.C., E.G.S.); Department of Medicine, Division of Clinical Pharmacology, University of Western Ontario, London, Ontario, Canada (R.B.K.); and Department of Pharmaceutics, The University of Washington, Seattle, Washington (Y.S.L.)
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Rachel Scheib
Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee (K.Y., C.C., R.S., S.G., R.K.T., A.C., E.G.S.); Department of Medicine, Division of Clinical Pharmacology, University of Western Ontario, London, Ontario, Canada (R.B.K.); and Department of Pharmaceutics, The University of Washington, Seattle, Washington (Y.S.L.)
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Samit Ganguly
Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee (K.Y., C.C., R.S., S.G., R.K.T., A.C., E.G.S.); Department of Medicine, Division of Clinical Pharmacology, University of Western Ontario, London, Ontario, Canada (R.B.K.); and Department of Pharmaceutics, The University of Washington, Seattle, Washington (Y.S.L.)
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Ranjit K. Thirumaran
Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee (K.Y., C.C., R.S., S.G., R.K.T., A.C., E.G.S.); Department of Medicine, Division of Clinical Pharmacology, University of Western Ontario, London, Ontario, Canada (R.B.K.); and Department of Pharmaceutics, The University of Washington, Seattle, Washington (Y.S.L.)
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Amarjit Chaudhry
Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee (K.Y., C.C., R.S., S.G., R.K.T., A.C., E.G.S.); Department of Medicine, Division of Clinical Pharmacology, University of Western Ontario, London, Ontario, Canada (R.B.K.); and Department of Pharmaceutics, The University of Washington, Seattle, Washington (Y.S.L.)
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Richard B. Kim
Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee (K.Y., C.C., R.S., S.G., R.K.T., A.C., E.G.S.); Department of Medicine, Division of Clinical Pharmacology, University of Western Ontario, London, Ontario, Canada (R.B.K.); and Department of Pharmaceutics, The University of Washington, Seattle, Washington (Y.S.L.)
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Erin G. Schuetz
Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee (K.Y., C.C., R.S., S.G., R.K.T., A.C., E.G.S.); Department of Medicine, Division of Clinical Pharmacology, University of Western Ontario, London, Ontario, Canada (R.B.K.); and Department of Pharmaceutics, The University of Washington, Seattle, Washington (Y.S.L.)
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Abstract

P-glycoprotein (Pgp) [the product of the MDR1 (ABCB1) gene] at the blood-brain barrier (BBB) limits central nervous system (CNS) entry of many prescribed drugs, contributing to the poor success rate of CNS drug candidates. Modulating Pgp expression could improve drug delivery into the brain; however, assays to predict regulation of human BBB Pgp are lacking. We developed a transgenic mouse model to monitor human MDR1 transcription in the brain and spinal cord in vivo. A reporter construct consisting of ∼10 kb of the human MDR1 promoter controlling the firefly luciferase gene was used to generate a transgenic mouse line (MDR1-luc). Fluorescence in situ hybridization localized the MDR1-luciferase transgene on chromosome 3. Reporter gene expression was monitored with an in vivo imaging system following D-luciferin injection. Basal expression was detectable in the brain, and treatment with activators of the constitutive androstane, pregnane X, and glucocorticoid receptors induced brain and spinal MDR1-luc transcription. Since D-luciferin is a substrate of ABCG2, the feasibility of improving D-luciferin brain accumulation (and luciferase signal) was tested by coadministering the dual ABCB1/ABCG2 inhibitor elacridar. The brain and spine MDR1-luc signal intensity was increased by elacridar treatment, suggesting enhanced D-luciferin brain bioavailability. There was regional heterogeneity in MDR1 transcription (cortex > cerebellum) that coincided with higher mouse Pgp protein expression. We confirmed luciferase expression in brain vessel endothelial cells by ex vivo analysis of tissue luciferase protein expression. We conclude that the MDR1-luc mouse provides a unique in vivo system to visualize MDR1 CNS expression and regulation.

Footnotes

    • Received April 24, 2015.
    • Accepted August 12, 2015.
  • The work was supported by the National Institutes of Health National Institute of General Medicine [Grant R01 GM60346]; the National Institutes of Health National Cancer Institute [Cancer Center Support Grant P30 CA21765]; and the American Lebanese Syrian Associated Charities (ALSAC).

  • dx.doi.org/10.1124/dmd.115.065078.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (11)
Drug Metabolism and Disposition
Vol. 43, Issue 11
1 Nov 2015
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Research ArticleArticle

Human MDR1-luc CNS Reporter Mice

Kazuto Yasuda, Cynthia Cline, Yvonne S. Lin, Rachel Scheib, Samit Ganguly, Ranjit K. Thirumaran, Amarjit Chaudhry, Richard B. Kim and Erin G. Schuetz
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1646-1654; DOI: https://doi.org/10.1124/dmd.115.065078

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Research ArticleArticle

Human MDR1-luc CNS Reporter Mice

Kazuto Yasuda, Cynthia Cline, Yvonne S. Lin, Rachel Scheib, Samit Ganguly, Ranjit K. Thirumaran, Amarjit Chaudhry, Richard B. Kim and Erin G. Schuetz
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1646-1654; DOI: https://doi.org/10.1124/dmd.115.065078
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