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The Mutagenicity of Nitrosopeptides.

Blowers, Stephen David. (1992) The Mutagenicity of Nitrosopeptides. Doctoral thesis, University of Surrey (United Kingdom)..

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Abstract

Genetic toxicology assays have been used to investigate the mechanisms and modes of actions, both in vitro and in vivo, of a novel class of chemicals namely the diazo- and nitroso-peptides. The Salmonella typhimurium/mammalian microsome mutagenicity assay showed that most were direct acting mutagens. The nitrosopeptide, N-acetyl X prolile-N-nitrosoglycine (APNG) was taken as representative of the class. APNG was mutagenic in an in vivo rat bone marrow metaphase assay and a mouse micronucleus assay, after intraperitoneal (ip) treatments. In the mouse dominant lethal assay, after ip treatment, a high incidence of late deaths and malformations, was observed with no increase in early deaths. A host-mediated assay in mice, with the Salmonella typhimurium strain TA100, demonstrated that APNG was active after oral, as well as ip, treatment and provided a pharmacokinetic profile of the compound. The in vitro unscheduled DNA synthesis (UDS) assays demonstrated that APNG damaged DNA. A similar effect was seen in vivo and demonstrated that APNG was absorbed orally. Finally 32P post-labelling studies established that APNG formed stable adducts in rat liver and kidneys,after oral treatment. These results led to the supposition that APNG may be a carcinogen. This was confirmed in a restricted long-term mouse study where a variety of malignant tumour types were seen. It was concluded that the nitrosopeptide, APNG, had considerable carcinogenic potential and may cause heritable male germ cell damage. Also demonstrated was that by the careful selection of genetic toxicological studies the need for a large, and hence costly, carcinogenicity study was unnecessary.

Item Type: Thesis (Doctoral)
Divisions : Theses
Authors : Blowers, Stephen David.
Date : 1992
Additional Information : Thesis (Ph.D.)--University of Surrey (United Kingdom), 1992.
Depositing User : EPrints Services
Date Deposited : 24 Apr 2020 15:27
Last Modified : 24 Apr 2020 15:27
URI: http://epubs.surrey.ac.uk/id/eprint/854900

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