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

doi:10.1016/j.celrep.2017.10.026

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

Cell Rep. 2017 Oct 31;21(5):1304-1316. doi: 10.1016/j.celrep.2017.10.026.

Authors

Affiliations

¹ Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA.
² 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.
³ Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
⁴ 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.
⁵ Division of Biological Science, Graduate School of Science, Nagoya University, Japan.
⁶ Department of Anatomy, University of California San Francisco, San Francisco, CA, USA; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
⁷ Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.
⁸ Department of Anatomy, University of California San Francisco, San Francisco, CA, USA; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA. Electronic address: rdaneman@ucsd.edu.
⁹ Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA. Electronic address: roland.bainton@ucsf.edu.

Abstract

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.

Keywords: behavior; blood brain barrier; central nervous system; drug side effect mechanisms; drug transporters; endobiotics; steroid hormones; toxicology.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / chemistry
ATP Binding Cassette Transporter, Subfamily B / genetics
ATP Binding Cassette Transporter, Subfamily B / metabolism
ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
Aldosterone / chemistry
Aldosterone / metabolism
Animals
Behavior, Animal / drug effects
Binding Sites
Biological Evolution
Blood-Brain Barrier / drug effects
Blood-Brain Barrier / metabolism*
Brain / drug effects
Brain / metabolism
Central Nervous System / metabolism*
Cyclosporine / pharmacology
Databases, Chemical
Drosophila
Drosophila Proteins / chemistry
Drosophila Proteins / genetics
Drosophila Proteins / metabolism
Ecdysterone / chemistry
Ecdysterone / metabolism
Gonadal Steroid Hormones / analysis
Gonadal Steroid Hormones / metabolism*
Male
Molecular Docking Simulation
Rats
Substrate Specificity
Xenobiotics / chemistry
Xenobiotics / metabolism*

Substances

ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1
Drosophila Proteins
Gonadal Steroid Hormones
Xenobiotics
mdr65 protein, Drosophila
Aldosterone
Ecdysterone
Cyclosporine

Abstract

MeSH terms

Substances

Grants and funding