To clarify the pathogenesis of hepatic iron toxicity, we investigated the effect of chronic dietary iron overload on the expression of several genes in rat liver. After 10 wk of iron treatment, when only minor histological features of liver damage were appreciable, the level of pro-a.JI)-collagen mRNA was already higher than in control liver and increased further at 30 wk of treatment. Also, the relative amount of L ferritin subunit mRNA was enhanced early by iron load and was even more elevated at the latest time point considered, whereas neither H ferritin subunit nor transferrin mRNA levels were affected by iron treatment. In contrast, after chronic iron treatment, no variations were found in the steady-state level of mRNAs transcribed from liver-specific and preferentially expressed genes (albumin, a-fetoprotein, apolipoprotein A-1), growth-related genes (c-myc, c-Ha-ras and c-fos) and stress-induced genes (heat shock protein 70). These results suggest that chronic dietary iron overload in rats can specifically activate target genes in the liver (i.e., L ferritin and procollagen) in the absence of either histological signs of severe liver damage or alterations in differentiated liver functions. (HEPATOLOGY 1990;11:798-804.) Iron overload in the liver has been associated with hepatic fibrosis, cirrhosis and cancer (1, 2). The pathogenesis of liver damage has been recently defined in terms of iron-catalyzed free radical-mediated lipid peroxidation. Indeed, iron can initiate lipid peroxidative events in the cell by acting as a catalyst in the generation of reactive hydroxyl radicals (3) or by combining with oxygen to produce perferryl and ferry1 ions (4).
Experimental evidence for in uiuo occurrence of lipid peroxidation in subcellular organelles (mitochondria,