Abstract
The present study was performed to determine whether excess hepatic iron modulates the cancer-initiating and promoting properties of FB1. Thirty-eight male F344 rats were divided into four dietary treatment groups: (i) control diet (AIN, n=8); (ii) FB1 250 mg/kg diet (FB1, n=10); (iii) 1–2% carbonyl iron (CI, n=10); or (iv) FB1 plus iron loading (FB1/CI, n=10) for 5 weeks (2×2 factorial design). Hepatic iron concentrations in iron-loaded animals at 5 weeks were 444±56 (CI) and 479±80 μmol/g dry weight (FB1/CI) (mean±SEM). All the FB1-fed rats, in the presence or absence of CI, developed a toxic hepatitis with a 4-fold rise in serum alanine transaminase (ALT) levels. FB1 appeared to augment iron-induced hepatic lipid peroxidation, as measured by the generation of thiobarbituric acid reacting substances (TBARS) in liver homogenates (P<0.0001). Morphometric analysis showed that FB1 caused a significantly greater mean±SEM number of ‘enzyme-altered’ foci and nodules per cm2 (5.34±1.42 vs. 1.50±0.52, P<0.05), as well as a greater area (%) of liver occupied by foci and nodules (0.33±0.12% vs. 0.05±0.03%, P<0.001), compared with FB1/CI. The addition of FB1 to dietary iron loading caused a shift in distribution of iron from hepatocytes to Kupffer cells, probably due to phagocytosis of necrotic iron-loaded hepatocytes. In conclusion, (i) FB1 appears to cause toxicity in the liver independently from effects on lipid peroxidation; (ii) FB1 has a potentiating effect on iron-induced lipid peroxidation; and (iii) dietary iron loading appears to protect against the cancer promoting properties of FB1, possibly due to a stimulatory effect of iron on hepatocyte regeneration.
Published Version
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