5-Aminolevulinic acid induces iron release from ferritin.
5-Aminolevulinic acid (ALA), a heme precursor accumulated in acute intermittent porphyria (AIP) and lead poisoning, undergoes metal-catalyzed oxidation in air-equilibrated solutions buffered at neutral pH, yielding free radicals (O2, HO. and ALA.). The capacity of ALA to release iron from horse spleen and rat liver ferritin in vitro and to concomitantly initiate liposome lipid peroxidation was characterized. ALA induced iron release from ferritin in normally aerated solutions, in a dose (0.05-1 mM)- and time (0-120 min)-dependent manner; no reaction occurs under nitrogen. Superoxide dismutase partially inhibited (50% at 100 U/ml) iron release by 0.5 mM ALA, whereas the addition of catalase (50 U/ml) had no effect under these conditions. In phosphatidylcholine: cardiolipin (80:20) liposomes, and in the presence of 2 microM EDTA, ALA (0.025-1 mM) per se had a subtle effect on lipid peroxidation, while after addition of ferritin (0.25 mg/ml) there was a significant increase in lipid peroxidation as evaluated by dose-dependent formation of 2-thiobarbituric-reactive substances and diene conjugation. In vivo, iron accumulation in the liver of ALA-treated rats was observed. Altogether, these data demonstrate the ability of ALA-generated free radicals to release iron from ferritin and to affect iron metabolism in vivo. ALA-mediated iron release from ferritin, therefore, may aggravate oxidative damage to cell components and contribute to the pathology observed in AIP (eg., primary liver cancer) and lead poisoning.
Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina.
P I
PI
Oteiza
C G
CG
Kleinman
M
M
Demasi
E J
EJ
Bechara
D000622:Aminolevulinic Acid / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005293:Ferritins / Q000737:chemistry / Q000378:metabolism*; D005609:Free Radicals; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D015227:Lipid Peroxidation; D008081:Liposomes; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008956:Models, Chemical; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
D005609:Free Radicals; D008081:Liposomes; D017392:Thiobarbituric Acid Reactive Substances; D000622:Aminolevulinic Acid; D005293:Ferritins; D007501:Iron