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The mechanisms of toxic effects of divalent cations of three heavy metals Hg, Cd and Cu in rat ascites hepatoma AS-30D cells cultivated in vitro were compared. It was found that the toxicity of these ions, applied in the micromolar range (10–500 μM), decreased from Hg2+ (most toxic) to Cu2+ (least toxic). Hg2+ and Cd2+ produced a high percentage of cell death by both necrosis and apoptosis, whereas Cu2+ at concentrations up to 500 μM was weakly effective. Hg2+ at concentration of 10 μM appeared slightly uncoupling (i.e., stimulated resting state respiration and decreased the mitochondrial transmembrane potential), whereas it exerted a strong inhibitory effect on the respiratory chain and rapid dissipation of the membrane potential at higher concentrations. Cu2+ had inhibitory effect on cell respiration only at 500 μM concentration and after incubation of 48 h but produced a significant uncoupling effect at lower concentrations. Cu2+ induced an early and sharp increase of intracellular production of reactive oxygen species (ROS). The action of Hg2+ and Cd2+ on ROS generation was biphasic. They stimulated ROS generation within the cells at low concentrations and at short incubation times but decreased ROS generation at higher concentrations and at longer incubation. It is concluded that mitochondria are an important target for toxic effects of Hg2+, Cd2+ and Cu2+ in AS-30D rat hepatoma cells.