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Am J Physiol Lung Cell Mol Physiol 284: L298-L306, 2003. First published October 25, 2002; doi:10.1152/ajplung.00157.2002
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Vol. 284, Issue 2, L298-L306, February 2003

Delta 9-Tetrahydrocannabinol disrupts mitochondrial function and cell energetics

Theodore A. Sarafian, Shaghig Kouyoumjian, Farnaz Khoshaghideh, Donald P. Tashkin, and Michael D. Roth

Department of Medicine, Division of Pulmonary and Critical Care, Center for Health Sciences, University of California, Los Angeles, Los Angeles, California 90095

We have observed rapid and extensive depletion of cellular energy stores by Delta 9-tetrahydrocannabinol (THC) in the pulmonary transformed cell line A549. ATP levels declined dose dependently with an IC50 of 7.5 µg/ml of THC after 24-h exposure. Cell death was observed only at concentrations >10 µg/ml. Studies using JC-1, a fluorescent probe for mitochondrial membrane potential, revealed diminished mitochondrial function at THC concentrations as low as 0.5 µg/ml. At concentrations of 2.5 or 10 µg/ml of THC, a decrease in mitochondrial membrane potential was observed as early as 1 h after THC exposure. Mitochondrial function remained diminished for at least 30 h after THC exposure. Flow cytometry studies on cells exposed to particulate smoke extracts indicate that JC-1 red fluorescence was fivefold lower in cells exposed to marijuana smoke extract relative to cells exposed to tobacco smoke extract. Comparison with a variety of mitochondrial inhibitors demonstrates that THC produced effects similar to that of carbonyl cyanide p-trifluoromethoxyphenylhydrazone, suggesting uncoupling of electron transport. Loss of red JC-1 fluorescence by THC was suppressed by cyclosporin A, suggesting mediation by the mitochondrial permeability transition pore. This disruption of mitochondrial function was sustained for at least 24 h after removal of THC by extensive washing. These results suggest that exposure of the bronchopulmonary epithelium to THC may have important health and physiological consequences.

adenosine 5'-triphosphate; JC-1; marijuana; flow cytometry; mitochondrial membrane potential


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