Regulation of Cannabinoid Metabolism by Hepatic FABPs

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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.