Delta 9-tetrahydrocannabinol disrupts mitochondrial function and cell energetics.
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 IC(50) of 7.5 microg/ml of THC after 24-h exposure. Cell death was observed only at concentrations >10 microg/ml. Studies using JC-1, a fluorescent probe for mitochondrial membrane potential, revealed diminished mitochondrial function at THC concentrations as low as 0.5 microg/ml. At concentrations of 2.5 or 10 microg/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.
Sarafian
Theodore A
TA
Department of Medicine, Division of Pulmonary and Critical Care, Center for Health Sciences, University of California-Los Angeles, Los Angeles, CA 90095, USA. tsarafian@mednet.ucla.edu
Kouyoumjian
Shaghig
S
Khoshaghideh
Farnaz
F
Tashkin
Donald P
DP
Roth
Michael D
MD
D001562:Benzimidazoles; D002188:Cannabis; D002232:Carbocyanines; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002468:Cell Physiological Phenomena / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000008:administration & dosage / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects*; D005456:Fluorescent Dyes; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology*; D009994:Osmolar Concentration; D011619:Psychotropic Drugs / Q000008:administration & dosage / Q000494:pharmacology*; D012906:Smoke / Q000009:adverse effects; D014407:Tumor Cells, Cultured; D014475:Uncoupling Agents / Q000494:pharmacology
D001562:Benzimidazoles; D002232:Carbocyanines; D005456:Fluorescent Dyes; D011619:Psychotropic Drugs; D012906:Smoke; D014475:Uncoupling Agents; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D013759:Dronabinol