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Doctoral Thesis
DOI
10.11606/T.46.2018.tde-18092018-155702
Document
Author
Full name
Lia Sumie Nakao
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2002
Supervisor
Committee
Augusto, Ohara (President)
Leitão, Alvaro Augusto da Costa
Leite, Luciana Cezar de Cerqueira
Menck, Carlos Frederico Martins
Monteiro, Hugo Pequeno
Title in Portuguese
Metabolimos radicalares do etanol e alquilação de ácidos nucleicos estudos in vitro e in vivo
Keywords in Portuguese
Acetaldeído
Carcinogênese
Danos a ácidos nucléicos
Metabolismo do etanol
Oxidação (Metabolismo)
Radicais livres
Xenobiótico (Estudo)
Abstract in Portuguese
O consumo de álcool vem sendo associado a um aumento do risco de câncer e a uma situação de estresse oxidativo. Os metabólitos responsáveis por tais processos permanecem em discussão. Neste trabalho, caracterizamos novos metabólitos radicalares do etanol e examinamos suas interações com ácidos nucléicos. Primeiramente, demonstramos que os radicais 1-hidroxietila e 2-hidroxietila produzidos durante a oxidação do etanol por sistemas Fenton alquilam DNA e RNA in vitro produzindo os adutos 8-(1-HE)Gua e 8-(2-HE)Gua, respectivamente. Esses adutos foram sintetizados e caracterizados quimicamente. Também, demonstramos que acetaldeído, o principal metabólito do etanol, é oxidado por sistemas Fenton, peroxinitrito, xantina oxidase, partículas submitocondriais e ratos a radicais acetila e metila. Esses radicais foram caracterizados e seus mecanismos de formação elucidados, pelo menos in vitro. A possibilidade do radical 1-hidroxietila alquilar ácidos nucléicos in vivo foi também examinada. Inesperadamente, o aduto 8-(1-HE)Gua foi detectado em RNA e DNA do fígado de ratos controle e seus níveis não foram significativamente alterados após administração aguda de etanol. Esses resultados sugerem que os radicais 1-hidroxietila, acetila e metila são importantes metabólitos do etanol in vivo mas atacam preferencialmente outras biomoléculas que não ácidos nucléicos.
Title in English
Ethanol radicals and nucleic acid alkylation studies in vitro and in vivo studies
Keywords in English
Acetaldehyde
Carcinogenesis
Ethanol metabolism
Free radicals
Nucleic acid damage
Oxidation (Metabolism)
Xenobiotic (Study)
Abstract in English
Alcohol consumption has been associated with increased cancer risk and an oxidative stress condition. Ethanol metabolites responsible for these processes remain debatable. Here, we characterized novel radical metabolites of ethanol and examined their interactions with nucleic acids. First, we demonstrated that the 1-hydroxyethyl and 2-hydroxyethyl radical produced from ethanol oxidation by Fenton systems alkylated DNA and RNA in vitro to produce 8-(1HE)Gua and 8-(2-HE)Gua, respectively. Both adducts were synthesized and structurally characterized. Next, we demonstrated that acetaldehyde, the main ethanol metabolite, is oxidized by Fenton systems, peroxynitrite, xanthine oxidase, submitochondrial particles and whole rats to acetyl and methyl radicals. These radicals were characterized and their production mechanisms in vitro elucidated. The possibility of the 1-hydroxyethyl radical alkylating nucleic acids in vivo was also examined. Unexpectedly, the adduct 8-(1-HE)Gua was detected in RNA and DNA from liver of control rats and their levels were not increased by acute ethanol treatment. Overall, the results suggest that the radicals 1-hydroxyethyl, acetyl and methyl are important ethanol metabolites in vivo but they preferentially attack biomolecules other than nucleic acids.
 
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Publishing Date
2018-09-18
 
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