Iron mobilization by succinylacetone methyl ester in rats. A model study for hereditary tyrosinemia and porphyrias characterized by 5-aminolevulinic acid overload

Accumulation of Ei-aminolevulinic acid (ALA) is an event characteristic of porphyrias that may contribute to their pathological manifestations. To inv estigate effects of ALA independent of porphyrin accumulation we treated ra ts with the methyl eater of succinylacetone, an inhibitor of 5-aminolevulin ic acid dehydratase that accumulates in the porphyric-like syndrome heredit ary tyrosinemia. Acute 2-day treatment of fasted rats with succinylacetone methyl ester (SAME) promoted a 27% increase in plasma ALA. This increase in plasma AI,A was accompanied by augmentation of the level of total nonheme iron in liver (37%) and brain (20%). Mobilization of iron was also indicate d by 49% increase in plasma iron and a 77% increase in plasma transferrin s aturation. Liver responded with a mild (12%) increase in ferritin. Under th ese acute conditions, some indications of oxidative stress were evident: a 15% increase in liver reactive protein carbonyls, and a 42% increase in bra in subcellular membrane TEARS. Brain also showed a 44% increase in CuZnSOD activity, consistent with observations in treatment with ALA. Overall, the data indicate that SAME promotes ALA-driven changes in iron metabolism that could lead to increased production of free radicals. The findings support other evidence that accumulation of ALA in porphyrias and hereditary tyrosi nemia may induce iron-dependent biological damage that contributes to neuro pathy and hepatoma.