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| Author(s): |
Janice Onuki
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) |
| Defense date: | 2000-08-01 |
| Examining board members: |
Paolo Di Mascio;
Luiz Henrique Catalani;
Elizabeth Angelica Leme Martins;
Carlos Frederico Martins Menck;
Hugo Pequeno Monteiro
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| Advisor: | Paolo di Mascio |
| Abstract | |
5-Aminolevulinic acid (ALA) is a heme precursor accumulated in some inborn (acute intermittent porphyria-AIP and tyrosinosis) or acquired (lead poisoning) types of hepatic porphyria. In AIP patients, ALA is overproduced and accumulated in the liver. Liver biopsy samples of AIP patients revealed mitochondrial and endoplasmic reticulum structural alterations and accumulation of lipofucsin, fat and ferritin bodies. Mitochondrial mutations induced by pro- oxidants were suggested to contribute to cellular aging and cancer. These findings may be connected to the higher frequency of hepatocellular carcinoma (HCC) associated to symptomatic AIP patients. In vitro, ALA produces reactive oxygen species (ROS) upon metal- catalyzed oxidation and can be viewed as a deleterious endogenous source of ROS, triggering oxidative damage to cell structures and organs and being involved in the initiation and promotion of cancer. Besides, the final oxidation product of ALA, the 4,5-dioxovaleric acid (DOVA) is expect to induce DNA base modifications as already shown for other reactive carbonyl derivatives. In this study we demonstrated that ALA is able to produce DNA lesions such as strand breaks in plasmid DNA, increased steady state level of 8-oxo-7,8- dihydro-2\'-deoxyguanosine and 5-hydroxy-2´-deoxycytidine in rat organs DNA of ALA-treated rats and increased formation of several modified DNA bases in calf thymus DNA. 4,5-Dioxovaleric acid was showed to react with 2\'-deoxyguanosine and isolated calf thymus DNA through Schiff?s base formation to produce two diastereisomeric adducts. Aminolevulinic acid and DOVA were able to increase mutagenicity of the S. typhimurim strain TA104 and induce SOS response in E. coli PQ37. The mitochondrial and nuclear DNA damage were also detected by quantitative polymerase chain reaction technique in transformed human fibroblasts treated with ALA. All these data provide additional information on the genotoxic potential of ALA and reinforce the hypothesis that ALA may be involved in the induction of HCC in symptomatic AIP patients. (AU) | |