Abstract

Chromatographically pure Δ⁹-tetrahydrocannabinol (Δ⁹-THC) was tested in vitro for inhibitory activity on sodium- and potassium-stimulated ATPase (ATP phosphohydrolase, EC 3.6.1.3) from various sources. Concentrations of 3 µM Δ⁹-THC inhibited by 50% enzyme preparations with specific activities of 1200-1500 nmoles of P_i per minute per milligram of protein. Rat brain ATPases were much more sensitive to Δ⁹-THC than to equal concentrations of ouabain. The kinetics of inhibition of electric eel ATPases seemed to be noncompetitive with respect to ATP. Rat brain ouabain-insensitive ATPases were also inhibited by Δ⁹-THC, and preliminary kinetic data indicated that inhibition is competitive with respect to ATP. In Ehrlich ascites tumor cells (10⁷ cells/ flask), 60 µM Δ⁹-THC inhibited nucleoside ([³H]thymidine) incorporation without exerting any significant effect on the viability of cells as measured by O₂ consumption. Particulate ATPases isolated from cells exposed to Δ⁹-THC were found to have significantly lower specific activity than cells in control media, 123 ± 36 compared with 172 ± 16 nmoles of P_i per minute per milligram of protein (p < 0.005, n = 16). The hypothesis is advanced that several of the observed physiological effects of Δ⁹-THC can be explained on the basis of its ATPase-inhibitory activity.