Age-Associated Increase in Ferritin Content of Male Rat Liver: Implication for Diquat-Mediated Oxidative Injury

Abstract

Our previous studies in rat hepatocytes demonstrated an age-dependent increase in sensitivity to diquat-induced cytotoxicity, possibly as a result of increased iron availability. The present study was conducted to determine whether quantitative or qualitative changes in hepatic ferritin occur as a consequence of aging and whether diquat-mediated oxidation is intensified by elevated ferritin concentrations. Hepatic ferritins were isolated from male Fischer 344 rats ages 5, 15, and 25 months. Age-associated increases were observed in amounts of ferritin protein and ferritin iron per gram of liver, but there were no differences in proportions of H to L subunits or in rates of diquat-mediated iron release. The consequences of a threefold increase in ferritin content for diquat-mediated lipid peroxidation and protein carbonyl formation were examined in microsomal incubation systems. The addition of isolated rat liver ferritin augmented diquat-mediated oxidative damage in a time- and concentration-dependent manner, and the inclusion of deferoxamine completely inhibited the stimulation by ferritin. The results indicate that availability of ferritin iron is an important determinant of diquat-mediated oxidative injury and support the hypothesis that elevated hepatic ferritin content is responsible, at least in part, for the age-associated enhancement of diquat-induced toxicity.