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

• Published in: Cell reports (Cambridge) Vol. 21; no. 5; pp. 1304 - 1316
• Main Authors: Hindle, Samantha J., Munji, Roeben N., Dolghih, Elena, Gaskins, Garrett, Orng, Souvinh, Ishimoto, Hiroshi, Soung, Allison, DeSalvo, Michael, Kitamoto, Toshihiro, Keiser, Michael J., Jacobson, Matthew P., Daneman, Richard, Bainton, Roland J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 31-10-2017; Elsevier
• Subjects: Aldosterone - chemistry; Aldosterone - metabolism; Animals; 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; behavior; Behavior, Animal - drug effects; Binding Sites; Biological Evolution; blood brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain - drug effects; Brain - metabolism; central nervous system; Central Nervous System - metabolism; Cyclosporine - pharmacology; Databases, Chemical; Drosophila; Drosophila Proteins - chemistry; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; drug side effect mechanisms; drug transporters; Ecdysterone - chemistry; Ecdysterone - metabolism; endobiotics; Gonadal Steroid Hormones - analysis; Gonadal Steroid Hormones - metabolism; Male; Molecular Docking Simulation; Rats; steroid hormones; Substrate Specificity; toxicology; Xenobiotics - chemistry; Xenobiotics - metabolism; blood brain barrier; toxicology; drug transporters; endobiotics; steroid hormones; drug side effect mechanisms; behavior; central nervous system
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.10.026

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.
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•Blood-brain barrier ABC drug transporters regulate CNS levels of steroids•Blood-brain barrier ABC drug transporters regulate whole animal behavior•Stress-related drug side-effects are associated with the ABC drug transporter Mdr1•Competitive Mdr1 drug/steroid interactions may shed light on adverse drug reactions
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.