Regulation of Cannabinoid Metabolism by Hepatic FABPs

肝脏 FABP 对大麻素代谢的调节

• 批准号: 9333074
• 负责人: Matthew William Elmes
• 金额: $ 3.38万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-13 至 2018-08-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333074
• 关键词: Ablation; Absence of pain sensation; Address; Affect; Affinity; Animals; Behavior monitoring; Behavioral; Binding; Binding Proteins; Body Temperature; Body measure procedure; Brain; Cannabidiol; Cannabinoids; Catalepsy; Cells; Cellular Membrane; Clinical; Coupled; Cytochrome P450; Drug Interactions; Drug Kinetics; Drug usage; Enzymes; Exhibits; FABP1 gene; Fatty Acid-Binding Protein 1; Gender; Genetic; Goals; Hepatic; Hepatocyte; Human; Hydrophobicity; In Vitro; Knockout Mice; Knowledge; Liver; Mediating; Medical Marijuana; Medicine; Metabolic; Metabolic Biotransformation; Metabolism; Monitor; Motor Activity; Mus; Nature; Outcome; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Physiologic Monitoring; Physiological; Primary Cell Cultures; Production; Protein Inhibition; Protein Isoforms; Proteins; Publications; Regulation; Research Personnel; Research Project Grants; Role; Site; Testing; Tetrahydrocannabinol; Time; Wild Type Mouse; Work; Xenobiotics; career; design; exogenous cannabinoid; fatty acid-binding proteins; gender difference; in vivo; inhibitor/antagonist; lipophilicity; liquid chromatography mass spectrometry; liver metabolism; metabolomics; natural hypothermia; novel; phytocannabinoid; sex; uptake

Project Summary The increasing clinical use of cannabinoids highlights the importance of developing a more complete understanding of cannabinoid pharmacokinetics and predicting potential drug-drug interactions of cannabinoids with other commonly prescribed medications. Following administration, cannabinoids including ∆9- tetrahydrocannabinol (THC) are metabolized and inactivated by cytochrome P450 enzymes primarily within the liver. These metabolic enzymes are solely located intracellularly, yet cannabinoids localize to cellular membranes as a result of their highly hydrophobic nature. A protein-mediated cytoplasmic transport mechanism must exist to shuttle cannabinoids into the cell for subsequent metabolism. Cannabinoid transport within hepatocytes remains poorly characterized, highlighting a major gap in our knowledge of phytocannabinoid inactivation. Identification of hepatic proteins that facilitate intracellular shuttling of exogenous cannabinoids would greatly enhance our knowledge of cannabinoid inactivation. The current proposal will test the hypothesis that hepatic fatty acid binding proteins (FABPs) mediate phytocannabinoid metabolism by shuttling these lipophilic compounds to their intracellular metabolic enzymes for subsequent biotransformation and elimination. In addition to phytocannabinoids, hepatic FABPs bind to and transport numerous clinically used drugs and therefore present a potential new site of drug-drug interactions. The principal goal of this research project is to test the hypothesis that hepatic FABPs influence THC pharmacokinetics and consequently the magnitude and duration of THC effects. In the first aim, the role of FABP1 in THC metabolism will be explored in vitro, utilizing primary hepatocytes derived from wild-type and FABP1 knockout mice. The second aim will characterize differences in cannabinoid metabolism and efficacy between wild-type and FABP1 knock out mice. Metabolite production will be examined by liquid chromatography mass spectrometry while THC efficacy will be examined by real-time monitoring of physiological and behavioral THC effects. The outcome of this work will identify FABPs as novel regulators of cannabinoid metabolism and may serve to predict drug-drug interactions caused by competition for binding, and subsequent uptake, at the FABPs.

项目摘要 大麻素的临床使用越来越多，这突出了开发更完整的 了解大麻素的药代动力学并预测大麻素的潜在药物相互作用 与其他常用处方药一起使用。在施用后，大麻素，包括109- 四氢大麻酚（THC）主要在体内被细胞色素P450酶代谢和灭活。 肝脏这些代谢酶仅位于细胞内，但大麻素定位于细胞内。 膜由于其高度疏水性的性质。一种蛋白质介导的细胞质转运 必须存在将大麻素穿梭到细胞中进行后续代谢的机制。大麻素转运 在肝细胞内的特征仍然很差，突出了我们对肝细胞的认识中的一个主要空白， 植物大麻素失活促进细胞内穿梭的肝蛋白的鉴定 外源性大麻素将大大增强我们对大麻素失活的认识。当前 一项提案将检验肝脂肪酸结合蛋白（FABP）介导植物大麻素的假设 通过将这些亲脂性化合物穿梭到它们的细胞内代谢酶进行随后的代谢， 生物转化和消除。除了植物大麻素，肝FABP结合并转运 许多临床上使用的药物，因此呈现了药物-药物相互作用的潜在新位点。 本研究项目的主要目标是检验肝脏FABPs影响THC的假设 药代动力学以及因此THC作用的幅度和持续时间。在第一个目标中， FABP 1在THC代谢中的作用将在体外进行研究，使用来自野生型和非野生型的原代肝细胞。 FABP 1敲除小鼠。第二个目标将描述大麻素代谢和功效的差异 在野生型和FABP 1敲除小鼠之间。将通过液体检查代谢产物的产生 THC的有效性将通过实时监测THC的浓度来检查。 生理和行为THC影响。这项工作的结果将确定FABPs作为新的监管机构， 大麻素代谢并可用于预测由结合竞争引起的药物-药物相互作用， 以及随后的吸收。