Structural and functional interaction of Δ9-tetrahydrocannabinol with liver fatty acid binding protein (FABP1)

Although serum Δ9-tetrahydrocannabinol (Δ9-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 Δ9-THC (Δ9-THC–OH) as well as Δ9-THC itself. Circular dichroism (CD) confirmed that not only Δ9-THC and Δ9-THC–OH but also downstream metabolites Δ9-THC–COOH and Δ9-THC–CO-glucuronide directly interact with FABP1. Δ9-THC and metabolite interaction differentially altered the FABP1 secondary structure, increasing total α-helix (all), decreasing total β-sheet (Δ9-THC–COOH, Δ9-THC–CO-glucuronide), increasing turns (Δ9-THC–OH, Δ9-THC–COOH, Δ9-THC–CO-glucuronide), and decreasing unordered structure (Δ9-THC, Δ9-THC–OH). Cultured primary hepatocytes from wild...