Plasma membrane inhibition of macromolecular precursor transport by THC

Abstract 10 −6 to 10 −4 M of delta-9-tetrahydrocannabinol (THC) or of other cannabinoids, which all have in common the C ring of olivetol, inhibit in cultured lymphocytes incorporation of [ 3 H]thymidine. The inhibitory effect of olivetol derivatives is related to their octanol-water partition coefficient (liposolubility). Within 15 min of incubation, THC inhibits precursor pool formation and macromolecular incorporation of thymidine, uridine and leucine. THC inhibits also [ 14 C] aminoisobutyric acid uptake into the cell, but does not alter the cellular “leakage” of this amino acid analogue. Using the isotopic dilution technique with L 1210 murine lymphoma cells and human lymphocytes, it was observed that THC decreases [ 3 H]thymidine uptake within fifteen seconds after addition of the drug to the culture. Experiments performed at 0° indicate that THC has no action on thymidine binding to the carrier. All of these observations suggest that THC in micromolar concentration inhibits DNA synthesis through a “non-specific” alteration of membrane configuration. This effect, due to the liposolubility of the drug, could induce eonfonnational changes of membrane-bound transport systems which would inhibit their function.