Structural and Functional Interaction of 9-Tetrahydrocannabinol with Liver Fatty Acid Binding Protein (FABP1).
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abstract
Although serum 9-tetrahydrocannabinol (9-THC) undergoes rapid hepatic clearance and metabolism, almost nothing is known regarding the mechanism(s) whereby this highly lipophilic phytocannabinoid is transported for metabolism/excretion. A novel NBD-arachidonoylethanolamide (NBD-AEA) fluorescence displacement assay showed that liver fatty acid binding protein (FABP1), the major hepatic endocannabinoid (EC) binding protein, binds the first major metabolite of 9-THC (9-THC-OH) as well as 9-THC itself. Circular dichroism (CD) confirmed that not only 9-THC and 9-THC-OH but also downstream metabolites 9-THC-COOH and 9-THC-CO-glucuronide directly interact with FABP1. 9-THC and metabolite interaction differentially altered the FABP1 secondary structure, increasing total -helix (all), decreasing total -sheet (9-THC-COOH, 9-THC-CO-glucuronide), increasing turns (9-THC-OH, 9-THC-COOH, 9-THC-CO-glucuronide), and decreasing unordered structure (9-THC, 9-THC-OH). Cultured primary hepatocytes from wild-type (WT) mice took up and converted 9-THC to the above metabolites. Fabp1 gene ablation (LKO) dramatically increased hepatocyte accumulation of 9-THC and even more so its primary metabolites 9-THC-OH and 9-THC-COOH. Concomitantly, rtPCR and Western blotting indicated that LKO significantly increased 9-THC's ability to regulate downstream nuclear receptor transcription of genes important in both EC ( Napepld > Daglb > Dagla, Naaa, Cnr1) and lipid ( Cpt1A > Fasn, FATP4) metabolism. Taken together, the data indicated that FABP1 may play important roles in 9-THC uptake and elimination as well as 9-THC induction of genes regulating hepatic EC levels and downstream targets in lipid metabolism.
