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.
Fraga
C G
CG
Departamento de Bioquímica, Universidade de São Paulo, Brazil.
Onuki
J
J
Lucesoli
F
F
Bechara
E J
EJ
Di Mascio
P
P
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