Neurobiology, Lipids
Fatty Acid-binding Proteins (FABPs) Are Intracellular Carriers for Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD)*

https://doi.org/10.1074/jbc.M114.618447Get rights and content
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Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) occur naturally in marijuana (Cannabis) and may be formulated, individually or in combination in pharmaceuticals such as Marinol or Sativex. Although it is known that these hydrophobic compounds can be transported in blood by albumin or lipoproteins, the intracellular carrier has not been identified. Recent reports suggest that CBD and THC elevate the levels of the endocannabinoid anandamide (AEA) when administered to humans, suggesting that phytocannabinoids target cellular proteins involved in endocannabinoid clearance. Fatty acid-binding proteins (FABPs) are intracellular proteins that mediate AEA transport to its catabolic enzyme fatty acid amide hydrolase (FAAH). By computational analysis and ligand displacement assays, we show that at least three human FABPs bind THC and CBD and demonstrate that THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs. Furthermore, we show that in contrast to rodent FAAH, CBD does not inhibit the enzymatic actions of human FAAH, and thus FAAH inhibition cannot account for the observed increase in circulating AEA in humans following CBD consumption. Using computational molecular docking and site-directed mutagenesis we identify key residues within the active site of FAAH that confer the species-specific sensitivity to inhibition by CBD. Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids. These data shed light on the mechanism of action of CBD in modulating the endocannabinoid tone in vivo and may explain, in part, its reported efficacy toward epilepsy and other neurological disorders.

Anandamide (N-Arachidonoylethanolamine) (AEA)
Cannabinoid
Endocannabinoid
Fatty Acid Binding Protein
Lipid Trafficking
Lipid Transport
Δ-tetrahydrocannabinol (THC)
Cannabidiol (CBD)
Cannabinoid Transporters
Fatty Acid Amide Hydrolase (FAAH)

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*

This work was supported, in whole or in part, by National Institutes of Health Grants DA032232, DA035923, DA035949, DA016419, DA026593, GM007518, GM008444, and NS042168.

1

These authors contributed equally to this work.

3

The abbreviations used are:

    THC

    Δ9-tetrahydrocannabinol

    CBD

    cannabidiol

    FABP

    fatty acid-binding protein

    2-AG

    2-arachidonoylglycerol

    AEA

    arachidonoylethanolamide

    FAAH

    fatty acid amide hydrolase

    PDB

    Protein Data Bank

    MD

    molecular dynamics.