Redox cycling and hepatotoxicity of diquat in aging male Fischer 344 rats.
The aim of this study was to determine the influence of aging on diquat-induced redox cycling in liver microsomes and diquat hepatotoxicity in rats. Diquat-stimulated production of superoxide anion radical and NADPH-cytochrome c (P-450) reductase activity were measured in liver microsomes prepared from male Fischer 344 rats at ages representing young adulthood (5-6 months), middle age (15-16 months), and old age (24-27 months). Both activities were decreased substantially (40%) in old rats. Diquat-induced liver damage was assessed 6 hr after the administration of diquat (0.1 mmol/kg, ip) on the basis of serum ALT and sorbitol dehydrogenase activities, hepatic microsomal cytochrome P-450 loss, and histological evaluation. The classical manifestations of hepatotoxicity in diquat-treated rats were as severe in old rats as in young-adult ones, despite the age-associated drop in redox cycling capacity. Diquat treatment also resulted in decreased concentrations of hepatic glutathione and ascorbic acid, increased concentrations of hepatic nonheme iron, and decreased liver weights. The changes in glutathione, nonheme iron, and liver weight were more pronounced in livers of middle-aged and old rats than in those of young-adult rats. These age-dependent differences could not be explained on the basis of plasma diquat concentrations, which were similar in the three age groups of rats. The absence of an effect of aging on the hepatotoxic effects of diquat indicates that redox cycling capacity is not limiting for the development of liver damage. Other effects of diquat were influenced by aging, but their relevancy to the hepatotoxicity is uncertain.