Specific inhibition of an acyltransferase by delta9-tetrahydrocannabinol

Increased phospholipid turnover in mouse lymphocytes during mitogen-induced blastogenesis can be prevented by low levels of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) invitro. Acyl CoA: lysophosphati-dylcholine acyltransferase, a lymphocyte plasma membrane enzyme, is inhibited by Δ⁹-THC with a K_i of 0.35 μM. Other cannabinoids with much lower psychoactivity inhibit the enzyme similarly only if present at more than 100 times the concentration needed for Δ⁹-THC inhibition. For cannabinoids other than Δ⁹-THC and for a variety of membrane-active lipids, the enzyme inhibition at higher concentrations of lipid correlates well with their anesthetic activity as measured by their ability to protect erythrocytes against hemolysis. However, the inhibition by Δ⁹-THC is much greater than that predicted by its anti-hemolytic activity, which indicates stereospecific requirements for inhibition of the enzyme. The inhibition of acyltransferase by Δ⁹-THC is not restricted to the lymphocyte enzyme and can also be demonstrated in mouse brain synaptosomes, suggesting a possible mechanism for psychoactive specificity.