Effect of theophylline on binding of delta-9-tetrahydrocannabinol with mammalian neuronal and non-neuronal membranes.

Delta-9-tetrahydrocannabinol (THC) (1.6 x 10(-6)-13.33 x 10(-6) M) binds to neuronal and non-neuronal subcellular membranes in a biphasic manner. Its binding to neuronal membranes occur in the following order synaptosome > myelin > brain microsome and brain mitochondria. Unlike brain membranes binding of delta-9-THC is greater with liver microsome than liver mitochondria. Irrespective of membranes theophylline (Th) (11.0 x 10(-6) and 550.0 x 10(-6) M) increases the binding of delta-9-THC by exposure of more number of delta-9-THC binding sites on the subcellular membranes without affecting its binding affinity. Failure of Th (11.0 x 10(-6)-550.0 x 10(-6) M) to increase the binding of delta-9-THC (1.6 x 10(-6)-13.33 x 10(-6) M) in solubilized membranes suggests the involvement of membrane lipid in the Th-induced enhancement of delta-9-THC binding.

Delta-9-tetrahydrocannabinol and theophylline: in vitro interaction with bovine serum albumin.

Delta-9-tetrahydrocannabinol (delta-9-THC) (1.6 x 10(-6) M-13.33 x 10(-6) M) and theophylline (11.0 x 10(-6) M-550.0 x 10(-6) M) both bind to bovine serum albumin (BSA) and the binding is linear with respect to concentration. Further, it is observed that delta-9-THC both at low (1.6 x 10(-6) M and 6.4 x 10(-6) M) and high (13.33 x 10(-6) M) concentrations inhibits the binding of theophylline to BSA; whereas theophylline (11.0 x 10(-6) M-550.0 x 10(-6) M) promotes the binding of delta-9-THC to BSA. Kinetic analysis (using Scatchard plots) shows that delta-9-THC (1.6-13.33 x 10(-6) M) reduces the high affinity binding constant (K1) and the number of low affinity binding sites (n2) of theophylline to BSA; while its low affinity binding constant (K2) increased without affecting the number of high affinity binding sites (n1) under identical conditions. Further, it is observed that at lower concentrations (1.6-6.4 x 10(-6) M) delta-9-THC exerts greater effect on the binding parameters of theophylline-BSA interactions as compared to the effect observed with its high concentration (13.33 x 10(-6) M). Theophylline (11.0-550.0 x 10(-6) M). on the other hand, increases the affinity of the binding of delta-9-THC to BSA without changing the number of its binding sites. These suggest that (a) delta-9-THC and theophylline bind at different sites of BSA molecules and (b) the two drugs interfere with each other in their individual binding with the molecular orientation of the BSA molecule.