Estudos in vivo e in vitro da induçäo da liberaçäo de ferro de ferritina promovida pelo ácido 5-aminolevulínico / Studies in vivo and in vitro of the induction of iron release from ferritin by promoted 5-aminolevulínic acid

Em alguns tipos de porfirias como porfiria aguda intermitente (PAI) e tirosinemia hereditária tipo (HT1) observa-se acúmulo do ácido 5-aminolevulínico (ALA) no sangue e tecidos. In vitro, o ALA sobre oxidaçäo pelo oxigênio molecular, catalisada por complexos de ferro, gerando o ácido 4,5-dioxovalérico (DOVA), íons NH4+, H2O2 e os radicais ALA, O2, e HO. ALA é capaz também de causar lesöes oxidativas a várias biomoléculas e inclusive induzir a liberaçäo de ferro de ferritina. Sendo assim, o ALA poderia agir como um pró-oxidante endógeno. Nossos estudos foram realizados com o objetivo de: 1) verificar a possibilidade de ocorrer processo autocatalítico durante a oxidaçäo do ALA em presença de ferritina de baço de cavalo (HoSF) e observar a influência de fosfato neste processo...

Oxidative stress in acute intermittent porphyria and lead poisoning may be triggered by 5-aminolevulinic acid

Highly reactive oxyradicals can be generated in vitro by iron-catalyzed aerobic oxidation of synthetic and naturally occuring substances capable of enolization in aqueous medium. Of biological interest are alfa-hydroxy- and alfa-aminocarbonyls such as carbohydrates, 5-aminolevulinic acid, and aminoacetone which tautomerize to the corresponding enediols and enolamines and yield oxyradicals initiated by electron transfer to dioxygen. Free radicals have been implicated in several normal and pathological processes. We briefly review our hypothesis of an in vivo prooxidant role of 5-aminolev-ulinic acid (ALA), the heme precursor accumulated in several porphyric disorders (e.g., lead poisoning, acute intermittent porphyria (AIP), tyrosinosis). Accordingly, i) ALA undergoes transition metal-catalyzed oxidation to give O-2, H2O2 and HO; ii) ALA induces iron release from ferritin, lipid peroxidation of cardiolipin-rich vesicles, single strand breaks in plasmid DNA, and guanosine oxidation in calf thymus DNA; iii) ALA causes Ca2+ -mediated rat liver mitochondria permeabilization; iv) rats chronically treated with ALA exhibit increased glycolytic metabolism; v) brain extracts of ALA-treated rats reveal increased levels of thiobarbituric acid reactive substances, direct chemiluminescence intensity, carbonyl proteins, ferritin, and "free iron"and gama-aminobutyric acid-receptor dissociation constant, and vi) patients with AIP and lead-exposed workers present augmented erythrocytic levels of the antioxidant enzymes superoxide dismutase and glutathione peroxidase. These data indicate the involvement of ALA-generated reactive species in the clinical manifestations (neuropathy, mental changes, muscle weakness, hepatoma) shared by the aforementioned inherited and acquired porphyric diseases.