5-Aminolevulinic acid mediates the in vivo and in vitro formation of 8-hydroxy-2'-deoxyguanosine in DNA.
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 +/- 23.3 residues/10(6) dG) was 4.5 times higher than in non-treated rats (21 +/- 7.5 residues/10(6) dG). In vitro exposure of calf thymus DNA to ALA (0.05-5 mM) in the presence of 10 microM Fe2+ caused the formation of 8-OHdG. The amount of 8-OHdG rose from 135 +/- 15 residues/10(6) dG in the control system to 1140 +/- 150 residues/10(6) dG after incubation with 5 mM ALA and 10 microM Fe2+. 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 microM) 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.
Departamento de Bioquímica, Universidade de São Paulo, Brazil.
C G
CG
Fraga
J
J
Onuki
F
F
Lucesoli
E J
EJ
Bechara
P
P
Di Mascio
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000622:Aminolevulinic Acid / Q000633:toxicity*; D000818:Animals; D002417:Cattle; D004247:DNA / Q000187:drug effects* / Q000378:metabolism*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D007501:Iron / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000209:etiology; D010084:Oxidation-Reduction; D017118:Porphyria, Acute Intermittent / Q000150:complications; D051381:Rats; D017208:Rats, Wistar
D000622:Aminolevulinic Acid; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D007501:Iron; D003849:Deoxyguanosine