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