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Bees have a crucial role in pollination; therefore, it is important to determine the causes of their recent decline. Fipronil and imidacloprid are insecticides used worldwide to eliminate or control insect pests. Because they are broad-spectrum insecticides, they can also affect honeybees. Many researchers have studied the lethal and sublethal effects of these and other insecticides on honeybees, and some of these studies have demonstrated a correlation between the insecticides and colony collapse disorder in bees. The authors investigated the effects of fipronil and imidacloprid on the bioenergetic functioning of mitochondria isolated from the heads and thoraces of Africanized honeybees. Fipronil caused dose-dependent inhibition of adenosine 5'-diphosphate-stimulated (state 3) respiration in mitochondria energized by either pyruvate or succinate, albeit with different potentials, in thoracic mitochondria; inhibition was strongest when respiring with complex I substrate. Fipronil affected adenosine 5'-triphosphate (ATP) production in a dose-dependent manner in both tissues and substrates, though with different sensitivities. Imidacloprid also affected state-3 respiration in both the thorax and head, being more potent in head pyruvate-energized mitochondria; it also inhibited ATP production. Fipronil and imidacloprid had no effect on mitochondrial state-4 respiration. The authors concluded that fipronil and imidacloprid are inhibitors of mitochondrial bioenergetics, resulting in depleted ATP. This action can explain the toxicity of these compounds to honeybees.

1 We evaluated the eects of the phenothiazine derivative thioridazine on mechanisms of mitochondria potentially implicated in apoptosis, such as those involving reactive oxygen species (ROS) and cytochrome c release, as well as the involvement of drug interaction with mitochondrial membrane in these eects. 2 Within the 0 ± 100 mM range thioridazine did not reduce the free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH) nor did it chelate iron. 3 However, at 10 mM thioridazine showed important antioxidant activity on mitochondria, characterized by inhibition of accumulation of mitochondria-generated O 2 .7, assayed as lucigeninderived chemiluminescence, inhibition of Fe 2+ /citrate-mediated lipid peroxidation of the mitochondrial membrane (LPO), assayed as malondialdehyde generation, and inhibition of Ca 2+ /t-butyl hydroperoxide (t-BOOH)-induced mitochondrial permeability transition (MPT)/protein-thiol oxidation, assayed as mitochondrial swelling. 4 Thioridazine respectively increased and decreased the¯uorescence responses of mitochondria labelled with 1-aniline-8-naphthalene sulfonate (ANS) and 1-(4-trimethylammonium phenyl)-6 phenyl 1,3,5-hexatriene (TMA-DPH). 5 The inhibition of LPO and MPT onset correlated well with the inhibition of cytochrome c release from mitochondria. 6 We conclude that thioridazine interacts with the inner membrane of mitochondria, more likely close to its surface, acquiring antioxidant activity toward processes with potential implications in apoptosis such as O 2 .7 accumulation, as well as LPO, MPT and associated release of cytochrome c.

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We described the effects of nimesulide (N-[4-nitro-2-phenoxyphenyl]-methanesulfonamide) and its reduced metabolite in isolated rat hepatocytes. Nimesulide stimulated the succinatesupported state 4 respiration of mitochondria, indicating an uncoupling effect of the drug. Incubation of hepatocytes with nimesulide (0.1-1 mM) elicited a concentration-and time-dependent decrease in cell viability as assessed by lactate dehydrogenase leakage, a decrease of mitochondrial membrane potential as assessed by rhodamine 123 retention, and cell ATP depression. Nimesulide also decreased the levels of NAD(P)H and glutathione in hepatocytes, but the extent of the effects was less pronounced in relation to the energetic parameters; in addition, these effects did not imply the peroxidation of membrane lipids. The decrease in the viability of hepatocytes was prevented by fructose and, to a larger extent, by fructose plus oligomycin; it was stimulated by proadifen, a cytochrome P450 inhibitor. In contrast, the reduced metabolite of nimesulide did not present any of the effects observed for the parent drug. These results indicate that: 1) nimesulide causes injury to the isolated rat liver cells, 2) this effect is mainly mediated by impairment of ATP production by mitochondria due to uncoupling, and 3) on account of the activity of its nitro group, the parent drug by itself is the main factor responsible for its toxicity to the hepatocytes.

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