Chemical carcinogenesis by dimethylnitrosamine : the influence of nutritional status of age

Detta är en avhandling från Stockholm : Stockholm University

Sammanfattning: Dimethylnitrosamine (DMN) is a potent carcinogen in a variety of animal species. Nitrosamines are widely spread in the environment and many populations of the world are continuously exposed to low doses of them. Dietary deficiency might strongly influence the capacity of the body to metabolize and excrete chemical carcinogens. DMN is mainly metabolized in the liver giving rise to alkylating species which can react with cellular components such as proteins and nucleic acids. The alkylation of the DNA molecule is thought to lead to the carcinogenic transformations caused by DMN.In this study the effects of DMN metabolism among nuclear components were studied in relation to diet and age and also between different tissues in mice.The alkylation of DNA and chromatin proteins was non-randomly distributed within liver nuclei in DMN-treated mice. Chromatin regions enriched in transcriptional activity were more accessible to the alkylating species derived from DMN than less active parts of the chromatin organization. This correlated with the inhibition by DMN of RNA polymerase II-mediated transcription activity which was most pronounced in the transcriptionally active chromatin regions.Dietary shortage in essential amino acids enhanced the level of the promutagenic lesion 0-methylguanine in liver DNA after a single dose of DMN. The deficient diets also resulted in a decreased level of the enzyme, Og-methylguanine-DNA methyl transferase, responsible for the repair of 0-methylguanine. There were age-related differences in the level of the repair enzyme in animals fed an adequate amount of essential amino acids, with adult mice having twice the level of subadult mice. After dietary deficiency the amount of the repair enzyme decreased to the same level in both age groups. A continuous exposure to DMN potentiated the increase in 0-methylguanine and the decrease of its repair enzyme in animals fed amino acid deficient diets.Age-related, tissue-specific differences in the capacity to metabolize DMN were observed. Subadult mice fed the control diet had higher levels of 7-methylguanine in kidney and lung compared with adults. In response to dietary deficiency increased levels of 7-methylguanine were found in the lung of both age groups and in the kidneys of the adult animals alone.

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