Genotoxicity of 5-aminolevulinic and 4,5-dioxovaleric acids in the salmonella/microsuspension mutagenicity assay and SOS chromotest.
5-Aminolevulinic acid (ALA) is a heme precursor that accumulates in some porphyric disorders and in lead poisoning which can undergo metal-catalyzed oxidation producing reactive oxygen species and the keto-aldehyde, 4,5-dioxovaleric acid (DOVA). Evidence in vitro of ALA-induced DNA lesions suggests that ALA and DOVA have mutagenic potential that could possibly contribute to an increased frequency of hepatocellular carcinoma (HCC) in patients with acute intermittent porphyria (AIP). In this study, we evaluated the genotoxic potential of ALA and DOVA. In the absence of exogenous metabolic activation, ALA and DOVA were mutagenic in Salmonella typhimurium tester strain TA104. ALA was also mutagenic in S. typhimurium TA102, but not in TA98, TA100, or TA1535, indicating an oxidative mechanism. Removal of H(2)O(2) with catalase gave only partial protection, suggesting generation of other mutagenic species. Both ALA and DOVA damaged the DNA of Escherichia coli PQ37, inducing the SOS response detected by an increase in beta-galactosidase activity. These results verified the potential mutagenic activity of ALA and DOVA and reinforce the hypothesis that DNA damage induced by ALA may be associated with the development of HCC in individuals suffering from AIP.
Onuki
Janice
J
Instituto de Química, Departamento de Bioquímica, Universidade de São Paulo, São Paulo, Brazil.
Rech
Célia Maria
CM
Medeiros
Marisa H G
MH
de A  Umbuzeiro
Gisela
G
Di Mascio
Paolo
P
D000622:Aminolevulinic Acid / Q000633:toxicity*; D006801:Humans; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D013014:SOS Response, Genetics; D012486:Salmonella typhimurium / Q000235:genetics*; D014631:Valerates / Q000633:toxicity*
D009153:Mutagens; D014631:Valerates; C007509:4,5-dioxovaleric acid; D000622:Aminolevulinic Acid