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

Elmes, Matthew W.; Kaczocha, Martin; Berger, William T.; Leung, KwanNok; Ralph, Brian P.; Wang, Liqun; Sweeney, Joseph; Miyauchi, Jeremy Tetsuo; Tsirka, Stella E.; Ojima, Iwao; Deutsch, Dale G.

doi:10.1074/jbc.m114.618447

Cited by 258 publications

(245 citation statements)

References 72 publications

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“…Currently, there are no experimental data supporting that residual cannabinoids may directly occupy FAAH binding sites for [ 11 C]CURB. In this regard, although CBD, among many constituents of cannabis, was identified as a moderate (IC50=15 µM) inhibitor of rodents FAAH (63), a recent study suggested that CBD does not inhibit human FAAH at the same concentrations (64). Nevertheless, residual cannabinoids in brain may modulate FAAH indirectly, e.g., through CB1 activation (65) or through disturbance of the structure and fluidity of lipid membrane where FAAH is located and influencing the activity of the enzyme non-specifically.…”

Section: Discussionmentioning

confidence: 99%

Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [11C]CURB

Boileau

Mansouri

Williams

et al. 2016

Biological Psychiatry

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Background One of the major mechanisms for terminating the actions of the endocannabinoid anandamide is hydrolysis by fatty acid amide hydrolase (FAAH) and inhibitors of the enzyme were suggested as potential treatment for human cannabis dependence. However, the status of brain FAAH in cannabis use disorder is unknown. Methods Brain FAAH binding was measured with positron emission tomography and [11C]CURB in 22 healthy control subjects and ten chronic, frequent cannabis users during early abstinence. The FAAH genetic polymorphism (rs324420) and blood, urine and hair levels of cannabinoids and metabolites were determined. Results In cannabis users FAAH binding was significantly lower by 14–20% across the brain regions examined as compared to matched control subjects (overall Cohen’s d=0.96). Lower binding was negatively correlated with cannabinoid concentrations in blood and urine and was associated with higher trait impulsiveness. Conclusions Lower FAAH binding levels in the brain may be a consequence of chronic and recent cannabis exposure and could contribute to cannabis withdrawal. This effect should be considered in the development of novel treatment strategies for cannabis use disorder that target FAAH and endocannabinoids. Further studies are needed to examine possible changes in FAAH binding during prolonged cannabis abstinence and whether lower FAAH binding predates drug use.

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Section: Discussionmentioning

confidence: 99%

Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [11C]CURB

Boileau

Mansouri

Williams

et al. 2016

Biological Psychiatry

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“…Computational analysis and ligand displacement assays suggest that CBD is transported by FABPs, which also transport AEA and so could explain the ability of CBD to increase AEA levels; the K i of CBD determined by displacement assays was in the region of 1.5-1.9 μM for 3 FABPs-which is comparable to AEA in the same assay (0.8-3.1 μM) [194]. FABPs are involved in intracellular trafficking of hydrophobic ligands within cells and are thus important in the transport of endogenous lipid and xenobiotics [236].…”

Section: Cbd Transporter Targets In Neurodegenerationmentioning

confidence: 92%

“…However, as discussed in the transporter section (see below), CBD may also bind to fatty acid binding proteins (FABPs), which could partly explain its apparent indirect effects on the ECS among others [194].…”

Section: Cbd Receptor Targets In Neurodegenerationmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

448

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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“…Although the mechanism of endocannabinoid (AEA, 2-AG) uptake across the plasma membrane is also not completely clear (74,75), AEA uptake appears to be driven by intracellular degradative enzymes (37,76). Much less is known about 2-AG uptake, except that it is saturable and blocking 2-AG hydrolysis does not alter the rate of 2-AG uptake (76,77).…”

mentioning

confidence: 99%

“…8). This model is based on the fact that Δ It is important to note that Δ 9 -THC is itself not an inhibitor of AEA hydrolysis by FAAH (37). Although FABP1 binds 2-AG and AEA more strongly than Δ…”

mentioning

confidence: 99%

Δ9-Tetrahydrocannabinol induces endocannabinoid accumulation in mouse hepatocytes: antagonism by Fabp1 gene ablation

McIntosh

Martin

Huang

et al. 2018

Journal of Lipid Research

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Phytocannabinoids, such as Δ9-tetrahydrocannabinol (THC), bind and activate cannabinoid (CB) receptors, thereby “piggy-backing” on the same pathway’s endogenous endocannabinoids (ECs). The recent discovery that liver fatty acid binding protein-1 (FABP1) is the major cytosolic “chaperone” protein with high affinity for both Δ9-THC and ECs suggests that Δ9-THC may alter hepatic EC levels. Therefore, the impact of Δ9-THC or EC treatment on the levels of endogenous ECs, such as N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), was examined in cultured primary mouse hepatocytes from WT and Fabp1 gene-ablated (LKO) mice. Δ9-THC alone or 2-AG alone significantly increased AEA and especially 2-AG levels in WT hepatocytes. LKO alone markedly increased AEA and 2-AG levels. However, LKO blocked/diminished the ability of Δ9-THC to further increase both AEA and 2-AG. In contrast, LKO potentiated the ability of exogenous 2-AG to increase the hepatocyte level of AEA and 2-AG. These and other data suggest that Δ9-THC increases hepatocyte EC levels, at least in part, by upregulating endogenous AEA and 2-AG levels. This may arise from Δ9-THC competing with AEA and 2-AG binding to FABP1, thereby decreasing targeting of bound AEA and 2-AG to the degradative enzymes, fatty acid amide hydrolase and monoacylglyceride lipase, to decrease hydrolysis within hepatocytes.

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

Cited by 258 publications

References 72 publications

Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [11C]CURB

Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [11C]CURB

Molecular Targets of Cannabidiol in Neurological Disorders

Δ9-Tetrahydrocannabinol induces endocannabinoid accumulation in mouse hepatocytes: antagonism by Fabp1 gene ablation

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