HEME PRECURSOR DELTA-AMINOLEVULINIC-ACID INDUCES ACTIVATION OF THE CYTOSOLIC IRON REGULATORY PROTEIN-1

Control of cellular iron homoeostasis is performed by iron regulatory protein 1 (IRP1) through post-transcriptional modifications. This prot ein is sensitive to intracellular iron availability, being activated a t low iron levels and inactivated at high iron levels, conditions that signal the increased expression of the transferrin receptor or of fer ritin respectively. IRP1 is known to be activated by some oxidants suc h as H2O2 and NO. delta-Aminolaevulinic acid (ALA), previously found t o produce reactive oxygen species and a carbon-centred radical, to rel ease iron from ferritin, and to increase rat liver and brain non-haem iron and ferritin, was investigated for its effects on IRP1 activity i n cultured hamster pulmonary fibroblasts. We have found that 1-2mM ALA produced a 2-3-fold activation of IRP. On incubation with 1-4 mM succ inylacetone methyl ester, a potent ALA dehydratase inhibitor, a 3-4-fo ld activation of the protein was observed, accompanied by a 40 % incre ase in the intracellular ALA concentration. When cells were incubated in the presence of ALA or succinylacetone methyl ester, N-acetylcystei ne inhibited IRP1 activation, suggesting that the observed effect is m ediated by an oxidative process. We surmise that ALA-induced IRP1 acti vation might act as a co-sensor of iron homoeostasis.