INHIBITION BY THC OF THYMIDINE TRANSPORT: A PLASMA MEMBRANE EFFECT

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 3H thymidine. The inhibitory effect of olivetol derivatives is related to their octanol-water partition coefficient (liposolubility). Within 15 minutes of incubation, THC inhibits precursor pool formation and macromolecular incorporation of thymidine, uridine and leucine. THC inhibits also 14C aminoisobutyric acid uptake into the cell, but does not alter the cellular “leakage” of this amino acid analogue. Using isotopic dilution technique with L1210 murine lymphoma cells and human lymphocytes, it was observed that THC decreases 3H thymidine uptake within fifteen seconds after addition of the drug to the culture. Experiments performed at 0°C 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 conformational changes of membrane bound transport systems which would inhibit their function.