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Title: Detection of DNA damage caused by N-nitrosoindoles
Author: Lucas, Lynda T.
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2001
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To evaluate the genotoxicity of N-nitrosoindoles, three model compounds, 1-nitrosoindole-3-acetonitrile (NIAN), 1-nitrosoindole-3-acetamide and l-nitrosoindole-3-acetic acid methyl ester, were reacted with isolated purine nucleotides at physiological pH. The profile of reaction products was identical for each of the N-nitrosoindoles. The results indicated that N-nitrosoindoles can efficiently transfer the nitroso group to nucleophilic targets in isolated purine nucleotides, causing depurination, deamination coupled with depurination to afford hypoxanthine and xanthine, and formation of a novel deoxyguanosine monophosphate analogue, 2'-deoxyoxanosine monophosphate and its corresponding depurination product, oxanine. These pathways of modification were preserved at the macromolecular level in oligonucleotides and calf thymus DNA, with guanine residues appearing to be a primary site of reaction. The studies revealed an additional cross-linked product at CG residues in NIAN-treated duplex DNA. Pyrimidine residues were inactive toward nitroso transfer by NIAN. The ability of the nitroso group to exert damage at the nuclei was demonstrated in vivo in the glandular stomach of CD-I mice via detection of abasic site damage, and in single cells in vitro as shown by the Comet assay. NIAN was mutagenic in the Ames II assay. In contrast to many other genotoxic N-nitrosocompounds, which are known to alkylate DNA, the genotoxicity of N-nitrosoindoles arises via efficient transnitrosation to nucleophilic sites on the purine bases. All of the products resulting from transnitrosation by N-nitrosoindoles are potentially mutagenic if they occur in vivo.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available