Fatty Acid-binding Proteins (FABPs) Are Intracellular Carriers for Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD)
Fatty Acid-binding Proteins (FABPs) Are Intracellular Carriers for Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD)
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DOI：
10.1074/jbc.m114.618447
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发表时间：
2015-04-03
影响因子：
4.8
通讯作者：
Deutsch, Dale G.
中科院分区：
文献类型：
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作者：
Elmes, Matthew W.;Kaczocha, Martin;Deutsch, Dale G.
δ（9）-四氢大麻酚（THC）和大麻二酚（CBD）天然存在于大麻（Cannabis）中，并且可以单独或组合配制在药物中，如Marinol或Sativex。虽然已知这些疏水化合物可以通过白蛋白或脂蛋白在血液中转运，但尚未鉴定出细胞内载体。最近的报告表明，CBD和THC在给予人类时会提高内源性大麻素anandamide（AEA）的水平，这表明植物大麻素靶向参与内源性大麻素清除的细胞蛋白。脂肪酸结合蛋白（Fatty Acid-binding proteins，FABPs）是一种细胞内蛋白质，介导AEA转运至其分解代谢酶脂肪酸酰胺水解酶（Fatty Acid amide Hydrolase，FAAH）。通过计算分析和配体置换试验，我们表明至少有三种人FABPs结合THC和CBD，并证明THC和CBD通过靶向FABPs抑制细胞对AEA的摄取和催化。此外，我们表明，与啮齿动物FAAH相比，CBD不会抑制人类FAAH的酶作用，因此FAAH抑制无法解释CBD消耗后观察到的人类循环AEA增加。使用计算分子对接和定点诱变，我们确定FAAH的活性位点内的关键残基，赋予物种特异性的CBD抑制的敏感性。对FABP的竞争可能部分或全部解释了消费大麻素后报告的内源性大麻素循环水平的增加。这些数据揭示了CBD在体内调节内源性大麻素的作用机制，并可以部分解释其对癫痫和其他神经系统疾病的疗效。
Delta(9)-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.