Effect of reactive oxygen species promoted by delta-aminolevulinic acid on porphyrin biosynthesis and glucose uptake in rat cerebellum.
1. delta-Aminolevulinic acid (ALA) has been reported to promote reactive oxygen species (ROS). Overproduction and accumulation of ALA, as it occurs in acute intermittent porphyria (AIP), can be the origin of an endogenous source of ROS, which can then exert their oxidative damage to cell structures. 2. To investigate the induction of lipid peroxidation by ALA, thiobarbituric acid reactive substances and conjugated diene formation were measured by using minimal tissue units (MTUs) obtained from rat cerebellum. Malondialdehyde levels increased with ALA concentration and incubation time (72% at 1.0 mM ALA and 127% at 4.0 mM ALA for 4 hr), and conjugated diene formation was enhanced 50% in incubations with 1.0 mM ALA for 4 hr. 3. ALA-promoted ROS by exposure of cerebellum MTUs to 1.0 mM ALA during different intervals (1-4 hr) was partly reduced by the addition of antioxidants such as superoxide dismutase (SOD; 50 U/ml), catalase (4.5 microM) and dimethylsulfoxide (150 mM), demonstrating the involvement of O2-., H2O2 and OH. in ALA autooxidation. 4. Porphobilinogen biosynthesis was 170% increased when cerebellum MTUs were incubated with 1.0 mM ALA for 4 hr in the presence of SOD, suggesting that protein damage was promoted by ALA autooxidation. 5. These findings provide the first experimental evidence of the involvement of ALA-promoted ROS in the damage of proteins related to porphyrin biosynthesis, specially ALA-D. Oxidation of this enzyme would lead to further accumulation of ALA in AIP patients, which may be the origin of the well-known neuropsychiatric manifestations.
Princ
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Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
Juknat
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Amitrano
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Batlle
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D000622:Aminolevulinic Acid / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D011166:Porphyrins / Q000096:biosynthesis; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D016166:Free Radical Scavengers; D011166:Porphyrins; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D000622:Aminolevulinic Acid; D005947:Glucose; D002118:Calcium