Iron mobilization by succinylacetone methyl ester in rats. A model study for hereditary tyrosinemia and porphyrias characterized by 5-aminolevulinic acid overload.
Accumulation of 5-aminolevulinic acid (ALA) is an event characteristic of porphyrias that may contribute to their pathological manifestations. To investigate effects of ALA independent of porphyrin accumulation we treated rats with the methyl ester of succinylacetone, an inhibitor of 5-aminolevulinic acid dehydratase that accumulates in the porphyric-like syndrome hereditary tyrosinemia. Acute 2-day treatment of fasted rats with succinylacetone methyl ester (SAME) promoted a 27% increase in plasma ALA. This increase in plasma ALA was accompanied by augmentation of the level of total nonheme iron in liver (37%) and brain (20%). Mobilization of iron was also indicated by 49% increase in plasma iron and a 77% increase in plasma transferrin saturation. Liver responded with a mild (12%) increase in ferritin. Under these acute conditions, some indications of oxidative stress were evident: a 15% increase in liver reactive protein carbonyls, and a 42% increase in brain subcellular membrane TBARS. 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 tyrosinemia may induce iron-dependent biological damage that contributes to neuropathy and hepatoma.
Rocha
M E
ME
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, SP, Brasil.
Bandy
B
B
Costa
C A
CA
de Barros
M P
MP
Pinto
A M
AM
Bechara
E J
EJ
D000622:Aminolevulinic Acid / Q000097:blood; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005293:Ferritins / Q000378:metabolism; D006537:Heptanoates / Q000494:pharmacology*; D007501:Iron / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008745:Methylation; D000623:Porphobilinogen Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism
D004791:Enzyme Inhibitors; D006537:Heptanoates; D017392:Thiobarbituric Acid Reactive Substances; D014168:Transferrin; C020804:succinylacetone; D000622:Aminolevulinic Acid; D005293:Ferritins; D007501:Iron; D013482:Superoxide Dismutase; D000623:Porphobilinogen Synthase