title: [Effect of diazoxide on the AS-30D rat ascites hepatoma cells treated by Cd2+].
abstract: For the last years, in several investigations, including ours, it was shown that oxidative stress and mitochondrial dysfunction mediated by disturbance of the mitochondrial respiratory chain and by induction of Ca2+ -dependent nonselective high-conductance pore of the inner mitochondrial membrane are involved in mechanism(s) of cytotoxic action of heavy metals. At the same time, possible interaction of heavy metals with other channels, in particular, with selective potassium channels, such as ATP-dependent potassium channels, which are generally considered to be protective for the cells, have not been studied. The aim of the present work was to examine the effect of diazoxide, an activator of mitochondrial ATP-dependent potassium channels, on mitochondrial physiology and cell survival in the presence of Cd2+. As a model system, we used AS-30D rat ascites hepatoma cells and isolated rat liver mitochondria. We found that diazoxide enhanced intracellular production of reactive oxygen species and induced significant stimulation of the resting respiration rate of the cells. Besides, diazoxide had a protective effect on AS-30D cells by increasing their survival that was substantially decreased in the presence of the tested concentrations of Cd2+ (50 and 100 microM). The protective effect of diazoxide was completely suppressed by increasing duration of incubation of the cells with Cd2+, and partially by addition to the assay medium of 5-hydroxyde- canoic acid (100 or 300 microM), a blocker of mitochondrial ATP-dependent potassium channels. In isolated rat liver mitochondria we found that diazoxide did not prevent the toxic action of Cd2+, since it produced no significant effects on the mitochondrial swelling and the respiration changes evoked by the heavy metal in the KCl assay media. Possible molecular mechanisms of the cytoprotective action of diazoxide are discussed.
authors.forename: E A
authors.initials: EA
authors.lastname: Beliaeva
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001201:Ascites / Q000378:metabolism / Q000473:pathology; D002104:Cadmium / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003981:Diazoxide / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008930:Mitochondria, Liver / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats
chemical_list: D000959:Antihypertensive Agents; D024101:Mitochondrial Proteins; D015221:Potassium Channels; D002104:Cadmium; D003981:Diazoxide