The perturbation of model membranes by (-)-delta 9-tetrahydrocannabinol. Studies using solid-state 2H- and 13C-NMR.
The effects of (-)-delta 9-tetrahydrocannabinol (delta 9-THC) on model phospholipid membranes were studied using solid-state 2H and 13C nuclear magnetic resonance spectroscopy. Aqueous multilamellar dispersions of dipalmitoylphosphatidylcholine with specific 2H- and 13C-labels as endogenous probes at the C7, methylene and the carbonyl groups, respectively, of the sn-2 chain were used to study the conformational and dynamic properties of the bilayer as a function of temperature and drug concentration. The drug molecule decreases the phase transition temperature of the bilayer in a concentration dependent manner up to 20 molar percent when full saturation has occurred. The 2H spectra show that delta 9-THC broadens the phase transition during which the spectra acquire a characteristic shape of a two-component system exchanging at an intermediate rate (approximately 10(6) s-1) with some liquid crystalline features. Such spectra provide information related to the melting of the phospholipid chains. At intermediate temperatures, the 13C spectra show a gel-like and a liquid-crystalline-like exchanging components and provide information about a conformational change at the phospholipid glycerol backbone occurring at or near the pretransition. The spectral composition and rate of exchange are both dependent on drug concentration. We have carried out computer simulations of the 13C spectra and obtained conformational information related to the phase transition process in the bilayer from gel to liquid crystal. Our studies show that delta 9-THC has a stronger effect on the sn-2 carbonyl near the bilayer interface than on the lipid chains and serve to describe the membrane perturbing effects of cannabinoids in molecular terms.
Makriyannis
A
A
School of Pharmacy and Institute of Materials Sciences, University of Connecticut, Storrs 06269.
Yang
D P
DP
Griffin
R G
RG
Das Gupta
S K
SK
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry*; D002247:Carbon Isotopes; D002462:Cell Membrane / Q000187:drug effects; D003198:Computer Simulation; D003903:Deuterium; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D008051:Lipid Bilayers / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D008968:Molecular Conformation; D013696:Temperature
D002247:Carbon Isotopes; D008051:Lipid Bilayers; D015060:1,2-Dipalmitoylphosphatidylcholine; D013759:Dronabinol; D003903:Deuterium; C025351:delta(9)-tetrahydrocannabinolic acid