Moderate iron overload enhances lipid peroxidation in livers of rats, but does not affect NF-κB activation induced by the peroxisome proliferator, Wy-14,643

It has been hypothesized that high concentrations of tissue iron may enhance carcinogenesis induced by free radical mechanisms. Wy-14,643 is a peroxisome proliferator that is hepatocarcinogenic in rats. Tumor induction may result in part from excessive production of reactive oxygen species, particularly H₂O₂. The purpose of this study was to examine the effect of iron status on oxidative stress and NF-κB activation in livers of rats treated with Wy-14,643. Forty-eight male Sprague-Dawley rats were fed one of four diets (20, 45, 650, 1500 mg Fe/kg diet) for 28 d. At the time of tissue collection, liver iron ranged from 1.4 to 9.9 μmol/g wet tissue in the diet groups. Wy-14,643 (0 or 0.1 g/100 g diet) was added to the diet for the final 10 d of the study. Wy-14,643 doubled the liver weight/body weight ratio (P = 0.0001), which was also increased by iron supplementation (P < 0.01). Iron supplementation increased thiobarbituric acid reactive substances and/or conjugated dienes, but there was no synergism between Wy 14,643 and iron on lipid peroxidation measures. The hepatic DNA binding activity of NF-κB was increased in rats administered Wy-14,643. However, differences in liver iron concentration did not alter activation of NF-κB in untreated rats or in those treated with Wy-14,643, DNA double-strand breakage was not affected by iron or Wy-14,643. In summary, although moderate changes in iron status altered liver lipid peroxidation, iron did not significantly increase oxidative stress induced by a hepatocarcinogenic peroxisome proliferator.