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-catalyze d aerobic oxidation of synthetic and naturally occurring substances ca pable of enolization in aqueous medium. Of biological interest are alp ha-hydroxy- and alpha-aminocarbonyls such as carbohydrates, 5-aminolev ulinic acid, and aminoacetone which tautomerize to the corresponding e nediols and enolamines and yield oxyradicals initiated by electron tra nsfer to dioxygen. Free radicals have been implicated in several norma l and pathological processes. We briefly review our hypothesis of an i n vivo prooxidant role of 5-aminolevulinic acid (ALA), the heme precur sor 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 an d HO .; ii) ALA induces iron release from ferritin, lipid peroxidation of cardiolipin-rich vesicles, single strand breaks in plasmid DNA, an d guanosine oxidation in calf thymus DNA; iii) ALA causes Ca2+-mediate d rat liver mitochondria permeabilization; iv) rats chronically treate d with ALA exhibit increased glycolytic metabolism; v) brain extracts of ALA-treated rats reveal increased levels of thiobarbituric acid rea ctive substances, direct chemiluminescence intensity, carbonyl protein s, ferritin, and ''free iron'' and gamma-aminobutyric acid-receptor di ssociation constant, and vi) patients with AIP and lead-exposed worker s present augmented erythrocytic levels of the antioxidant enzymes sup eroxide dismutase and glutathione peroxidase. These data indicate the involvement of ALA-generated reactive species in the clinical manifest ations (neuropathy, mental changes, muscle weakness, hepatoma) shared by the aforementioned inherited and required porphyric diseases.