Evolutionarily Conserved Roles for Blood-Brain Barrier Xenobiotic Transporters in Endogenous Steroid Partitioning and Behavior

Samantha J. Hindle; Roeben N. Munji; Elena Dolghih; Garrett Gaskins; Souvinh Orng; Hiroshi Ishimoto; Allison Soung; Michael DeSalvo; Toshihiro Kitamoto; Michael J. Keiser; Matthew P. Jacobson; Richard Daneman; Roland J. Bainton

Cell Reports (Oct 2017)

Evolutionarily Conserved Roles for Blood-Brain Barrier Xenobiotic Transporters in Endogenous Steroid Partitioning and Behavior

Samantha J. Hindle,
Roeben N. Munji,
Elena Dolghih,
Garrett Gaskins,
Souvinh Orng,
Hiroshi Ishimoto,
Allison Soung,
Michael DeSalvo,
Toshihiro Kitamoto,
Michael J. Keiser,
Matthew P. Jacobson,
Richard Daneman,
Roland J. Bainton

Affiliations

Samantha J. Hindle: Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA
Roeben N. Munji: Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA; Division of Clinical Pharmacology and Experimental Therapeutics, University of California San Francisco, San Francisco, CA, USA; Department of Anatomy, University of California San Francisco, San Francisco, CA, USA; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA
Elena Dolghih: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA
Garrett Gaskins: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA; Institute for Neurodegenerative Disease, University of California San Francisco, San Francisco, CA, USA; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
Souvinh Orng: Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA
Hiroshi Ishimoto: Division of Biological Science, Graduate School of Science, Nagoya University, Japan
Allison Soung: Department of Anatomy, University of California San Francisco, San Francisco, CA, USA; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA
Michael DeSalvo: Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA
Toshihiro Kitamoto: Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA
Michael J. Keiser: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA; Institute for Neurodegenerative Disease, University of California San Francisco, San Francisco, CA, USA; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
Matthew P. Jacobson: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA
Richard Daneman: Department of Anatomy, University of California San Francisco, San Francisco, CA, USA; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA; Corresponding author
Roland J. Bainton: Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA; Corresponding author

Journal volume & issue: Vol. 21, no. 5
pp. 1304 – 1316

Abstract

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Summary: Central nervous system (CNS) chemical protection depends upon discrete control of small-molecule access by the blood-brain barrier (BBB). Curiously, some drugs cause CNS side-effects despite negligible transit past the BBB. To investigate this phenomenon, we asked whether the highly BBB-enriched drug efflux transporter MDR1 has dual functions in controlling drug and endogenous molecule CNS homeostasis. If this is true, then brain-impermeable drugs could induce behavioral changes by affecting brain levels of endogenous molecules. Using computational, genetic, and pharmacologic approaches across diverse organisms, we demonstrate that BBB-localized efflux transporters are critical for regulating brain levels of endogenous steroids and steroid-regulated behaviors (sleep in Drosophila and anxiety in mice). Furthermore, we show that MDR1-interacting drugs are associated with anxiety-related behaviors in humans. We propose a general mechanism for common behavioral side effects of prescription drugs: pharmacologically challenging BBB efflux transporters disrupts brain levels of endogenous substrates and implicates the BBB in behavioral regulation. : Hindle et al. shed light on the curious finding that some drugs cause behavioral side-effects despite negligible access into the brain. These authors propose a unifying hypothesis that links blood-brain barrier drug transporter function and brain access of circulating steroids to common CNS adverse drug responses. Keywords: drug side effect mechanisms, central nervous system, blood brain barrier, behavior, toxicology, drug transporters, endobiotics, steroid hormones

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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