Hepatoprotective role of nitric oxide in an experimental model of chronic iron overload.

Abstract

Chronic iron overload (CIO) enhances nitric oxide (*NO) production in the liver, which may represent a hepatoprotective mechanism against CIO toxicity. In order to test this hypothesis, the influence of CIO (diet enriched with 3% (wt/wt) carbonyl-iron for 8 weeks) in the absence or presence of the (*)NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) on NOS activity, extracellular signal-regulated kinase (ERK1/2) and NF-kappaB activation was studied, in relation to ferritin expression and liver morphology. CIO increased liver NOS activity, ERK1/2 phosphorylation, NF-kappaB DNA binding, and ferritin expression, with normal liver histology. These changes were suppressed by combined CIO and L-NAME treatment, with the resulting inflammatory response of the liver. It is concluded that (*)NO response induced by CIO represents a molecular mechanism affording protection against iron toxicity, which is related to both the activation of the ERK/NF-kappaB pathway involving inducible NOS expression and ferritin upregulation, changes that may be interrelated.