5-Aminolevulinic acid mediates the in vivo and in vitro formation of 8-hydroxy-2'-deoxyguanosine in DNA

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Abstract
5-Aminolevulinic acid (ALA), a heme precursor accumulated in chemical and inborn porphyrias, may behave as an endogenous pro-oxidant In chronically treated rats (40 mg ALA/kg body wt every 2 days for 15 days) the steady-state level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in liver DNA (94.5 ± 233 residues/106 dG) was 4.5 times higher than in non-treated rats (21 ± 7.5 residues/ 106 dG). In vitro exposure of calf thymus DNA to ALA (0.05-5 mM) in the presence of 10 uM Fe2+ caused the formation of 8-OHdG. The amount of 8-OHdG rose from 135 ± 15 residues/106 dG in the control system to 1140 ± 150 residues/106 dG after incubation with 5 mM ALA and 10 µM Fe21. Diethylenetriaminepentaacetic acid (5 mM) or mannitol (100 mM) inhibited the formation of 8-OHdG by 63 and 69% respectively, evidencing the involvement of both H2O2 and HO in this process. Hydrogen peroxide (100 µM) or Fe2+ alone did not cause DNA oxidation. The present data support the hypothesis that ALA-generated reactive oxygen species can oxidize DNA and may be involved in the development of primary liver cell carcinoma in individuals with symptomatic acute intermittent porphyria.

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