Mineo Matsubara

The role of xanthine oxidase in paraquat intoxication

The role of xanthine oxidase in the mechanism of paraquat toxicity was assessed by in vitro and in vivo experiments. Paraquat stimulated the reduction of cytochrome c by xanthine-xanthine oxidase system in vitro. Paraquat, when added in vitro, stimulated hypoxanthine-dependent superoxide production in the cytosol of rat lung. Tungsten-feeding inhibits xanthine oxidase activity in a variety of tissues in experimental animals. Its therapeutic effect on paraquat intoxication was studied in this paper. In rats fed a tungsten-enriched diet for 5 weeks prior to intraperitoneal injection of 50 mg/kg paraquat dichloride, the mortality decreased significantly compared with rats fed a standard diet. Pretreatment with oxypurinol (1000 mg/kg, s.c.) also ameliorated the paraquat toxicity in rats. We conclude that xanthine oxidase plays an important role in paraquat toxicity and that xanthine oxidase inhibitors may become antidotes for paraquat intoxication.

Paraquat causes S-phase arrest of rat liver and lung cells in vivo

Abstract We examined the in vivo effect of paraquat on the cell cycle in rat liver and lung tissues and the protective effect of tungsten (a xanthine oxidase inhibitor) on paraquat toxicity. The bromodeoxy- uridine/propidium iodide double-staining method and flow cytometry were used for cell cycle assessment. Wistar rats were fed a standard diet or a tungsten-enriched diet were injected intravenously with 20 mg/kg paraquat, while uninjected rats served as controls. At 1, 3, and 5 days after paraquat injection, the liver and lungs were removed for examination following in vivo labeling with 20 mg/kg bromo- deoxyuridine for 1 h. Liver and lung cells were isolated and incubated with an anti-bromodeoxyuridine antibody and with propidium iodide for DNA staining. Flow cytometry showed that the S-phase cell populations in the liver and lungs of paraquat-injected rats fed a standard diet were increased markedly on days 1 and 3 after injection compared with the control levels. However, on day 5 the liver cells had nearly returned to normal, while the S-phase population remained high in the lungs. In contrast, the S-phase cell populations of liver and lung tissue showed no increase after paraquat injection in rats fed a tungsten-enriched diet. These findings suggest that paraquat-induced cytotoxicity is more prolonged in the lungs than in the liver. In addition, paraquat toxicity appears to be mediated by xanthine oxidase and xanthine oxidase inhibitors may be useful as an antidote.