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Lesions to biomolecules induced by 5-aminolevulinic acid and its derivatives

Grant number: 07/01966-5
Support Opportunities:Regular Research Grants
Duration: October 01, 2007 - April 30, 2010
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal Investigator:Janice Onuki
Grantee:Janice Onuki
Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil


5-Aminolevulinic acid (ALA) is a heme precursor accumulated, specially in the liver, in some porphyric disorders, such as acute intermittent porphyria (AIP) and plumbism, due to a decreased activity of porphobilinogen deaminase. Simptomatic patients of AIP present a increased incidence of hepatocellular carcinoma (HCC). In vitro, ALA can undergo metal-catalyzed oxidation producing reactive oxygen species which can cause oxidative damage to DNA and proteins, that could be involved in the initiation and promotion of cancer. The final product of ALA oxidation, the aldehyde, 4,5-dioxovaleric acid (DOVA), and its dimerization product, 3,6-dihydropyrazine-2,5-dipropanoic acid (DHPY) can also contribute to the deleterious effect of ALA. It has already been demonstrated that ALA is able to damage plasmid, calf thymus DNA and mitochondrial DNA in vitro, to increase the steady state level of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and 5-hydroxy-2’-deoxycytidine in liver DNA of ALA-treated rats. Formation of hydroxyl radical-induced modified DNA bases was also detected in calf thymus DNA. DOVA was able to produce DNA strand breaks and induce alkylation of the guanine moieties within both nucleoside and isolated DNA. ALA and DOVA showed to be mutagenic in Salmonella/microsome mutagenicity assay and Chromotest. The ALA dymerization product, 3,6-dihydropyrazine-2,5-dipropanoic acid also produced strand breaks and increase in 8-oxodGuo. This project will investigate the molecular mechanisms involved in biomolecules’ lesions induced by ALA and its derivatives to better understand the relationship between ALA and the higher incidence of HCC in AIP patients and also the possible side effects of ALA in the photodynamic therapy. The establishment of several Molecular Biology techniques represents a improvement and the investigation of toxins related to carcinogenic process could be initiated as a new investigation area in the Laboratory of Biochemistry and Biophysics. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MENEZES, P. R.; GONZALEZ, C. B.; DESOUZA, A. O.; MARIA, D. A.; ONUKI, J.. Effect of 5-aminolevulinic acid on the expression of carcinogenesis-related proteins in cultured primary hepatocytes. MOLECULAR BIOLOGY REPORTS, v. 45, n. 6, p. 2801-2809, . (10/51068-6, 07/01966-5)
MENEZES, PATRICIA REGINA; TRUFEN, CARLOS EDUARDO MADUREIRA; LICHTENSTEIN, FLAVIO; PELLEGRINA, DIOGO VIEIRA DA SILVA; REIS, EDUARDO MORAES; ONUKI, JANICE. Transcriptome profile analysis reveals putative molecular mechanisms of 5-aminolevulinic acid toxicity. Archives of Biochemistry and Biophysics, v. 738, p. 10-pg., . (10/51068-6, 07/01966-5)

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