Molecular Pharmacology, Vol 14, 130-137, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

On the Action of ⁹-Tetrahydrocannabinol as an Inhibitor of Sodium- and Potassium-Dependent Adenosine Triphosphatase

¹ Department of Biochemistry and Nutrition, University of Puerto Rico School of Medicine, San Juan, Puerto Rico 00936

Chromatographically pure ⁹-tetrahydrocannabinol (⁹-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 ⁹-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 ⁹-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 ⁹-THC, and preliminary kinetic data indicated that inhibition is competitive with respect to ATP. In Ehrlich ascites tumor cells (10⁷ cells/ flask), 60 µM ⁹-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 ⁹-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 ⁹-THC can be explained on the basis of its ATPase-inhibitory activity.

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ACKNOWLEDGMENTS We thank Professor L. S. Harris, Department of Pharmacology, Medical College of Virginia, for his generous gift of ⁹-THC, and Professor J. del Castillo, Neurobiology Institute, this institution, for the electric eels. We thank Drs. J. M. Cimadevilla and H. Jering for their criticisms and suggestions, and Mr. Juan Caloca for the illustrations.