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We examined whether superoxide is a factor responsible for paraquat-induced liver injury in terms of superoxide dismutase using cultured rat liver slices exposed to various concentrations of paraquat. The degree of liver injury was assessed by measurement of percentage of lactate dehydrogenase leakage into the medium and lipid hydroperoxides in the liver slices and by direct histopathological observation. Paraquat produced concentration- and time-related liver injury in the cultured rat liver slices. Notably, after exposure to 5 mmol/L paraquat, a significant increase of the percentage of lactate dehydrogenase leakage occurred from 4 hr (p < 0.05 vs. control group), and this gradually increased up to 8 hr (p < 0.01 and p < 0.001 vs. control group at 6 and 8 hr, respectively). Changes in lipid hydroperoxides in the liver slices were similar to those in percentage of lactate dehydrogenase leakage (p < 0.05 and p < 0.01 vs. control group at 6 and 8 hr, respectively). Liver injury was located around the central vein at 6 hr and gradually spread at 8 hr. Paraquat-induced liver injury was aggravated both biochemically and histopathologically by pretreatment with 5 mmol/L diethyldithiocarbamate, an inhibitor of copper- and zinc-containing superoxide dismutase activity (percentage of lactate dehydrogenase leakage: p < 0.01 and p < 0.001 vs. paraquat group at 6 and 8 hr, respectively; lipid hydroperoxides: p < 0.01 vs. paraquat group at 8 hr). Incubation of liver slices with liposome-encapsulated superoxide dismutase increased the augmentation of superoxide dismutase in the liver slices. Paraquat-induced liver injury was attenuated both biochemically and histopathologically by addition of an identical concentration of liposome-encapsulated superoxide dismutase (100 U/ml) (percentage of lactate dehydrogenase leakage: p < 0.01 and p < 0.01 vs. paraquat group at 6 and 8 hr, respectively; lipid hydroperoxides: p < 0.05 and p < 0.01 vs. paraquat group at 6 and 8 hr, respectively). However, the same concentration of free superoxide dismutase as that included in superoxide dismutase in liposome-encapsulated superoxide dismutase showed neither augmentation of superoxide dismutase in the liver slices nor hepatoprotection. These results suggest that superoxide is involved in the pathogenesis of paraquat-induced liver injury. (HEPATOLOGY 1990;14:707–714.) |
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