Is 5-aminolevulinic acid involved in the hepatocellular carcinogenesis of acute intermittent porphyria?
5-Aminolevulinic acid (ALA) is a heme precursor that accumulates in acute intermittent porphyria (AIP) due to enzymatic deficiencies in the heme biosynthetic pathway Its accumulation has been associated with several symptoms, such as abdominal pain attacks, neuromuscular weaknesses, neuropsychiatric alterations and increased hepatocellular carcinoma (HCC) incidence. The use of exogenous ALA to elevate porphyrin levels in tumor photodynamic therapy, adds further significance to ALA toxicology. Under ferritin mediated and metal catalyzed oxidation, ALA produces reactive oxygen species that can damage plasmid and isolated DNA in vitro, and increases the steady-state level of 8-oxo-7,8-dihydro-2'-deoxyguanosine in liver, spleen and kidney DNA and 5-hydroxy-2'-deoxycytidine in liver DNA of ALA-treated rats. The in vitro DNA damage could be partially inhibited by SOD, catalase, DTPA, mannitol and melatonin. ALA also promotes the formation of radical-induced base degradation products in isolated DNA. 4,5-Dioxovaleric acid, the final oxidation product of ALA, alkylates guanine moieties within both nucleoside and isolated DNA, producing two diastereoisomeric adducts. Dihydropyrazine derivatives of ALA generated by its dimerization, promote DNA strand-breaks and 8-oxodGuo formation in the presence of Cu2+. Together these results reinforce the hypothesis that the DNA damage induced by ALA may be associated with the development of HCC in individuals suffering from AIP.
Onuki
Janice
J
Departamento de Bioquímica, Instituto de Química, USP, São Paulo, Brasil.
Teixeira
Priscila C
PC
Medeiros
Marisa H G
MH
Dörnemann
Dieter
D
Douki
Thierry
T
Cadet
Jean
J
Di Mascio
Paolo
P
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000622:Aminolevulinic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004247:DNA / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D008113:Liver Neoplasms / Q000209:etiology*; D008670:Metals / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D017118:Porphyria, Acute Intermittent / Q000150:complications*; D011422:Propionates / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D051381:Rats; D014631:Valerates / Q000494:pharmacology
C449779:3,6-dihydropyrazine-2,5-dipropanoic acid; D008670:Metals; D011422:Propionates; D011719:Pyrazines; D014631:Valerates; C007509:4,5-dioxovaleric acid; D000622:Aminolevulinic Acid; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; C427203:calf thymus DNA; D003849:Deoxyguanosine