Mitochondrial and nuclear DNA damage induced by 5-aminolevulinic acid.
5-Aminolevulinic acid (ALA) is a heme precursor accumulated in plasma and in organs in acute intermittent porphyria (AIP), a disease associated with neuromuscular dysfunction and increased incidence of hepatocellular carcinoma (HCC). Liver biopsies of AIP patients showed odd-shaped mitochondria and autophagic vacuoles containing well-preserved mitochondria. ALA yields reactive oxygen species upon metal-catalyzed oxidation and causes in vivo and in vitro impairment of rat liver mitochondria and DNA damage. Using a quantitative polymerase chain reaction assay, we demonstrated that ALA induces a dose-dependent damage in nuclear and mitochondrial DNA in human SVNF fibroblasts and rat PC12 cells. CHO cells treated with ALA also show nuclear DNA damage and human HepG2 cells entered in apoptosis and necrosis induced by ALA and its dimerization product, DHPY. The present data provide additional information on the genotoxicity of ALA, reinforcing the hypothesis that it may be involved in the development of HCC in AIP patients.
Onuki
Janice
J
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Caixa Postal 26077 CEP 05513-970, São Paulo, SP, Brazil.
Chen
Yiming
Y
Teixeira
Priscila C
PC
Schumacher
Robert I
RI
Medeiros
Marisa H G
MH
Van Houten
Bennett
B
Di Mascio
Paolo
P
D000622:Aminolevulinic Acid / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016466:CHO Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004247:DNA / Q000187:drug effects* / Q000648:ultrastructure; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000648:ultrastructure; D022781:Hepatocytes / Q000187:drug effects* / Q000648:ultrastructure; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology* / Q000648:ultrastructure; D016716:PC12 Cells; D051381:Rats
D000622:Aminolevulinic Acid; D004247:DNA