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Molecular Interactions in the Assessment of the Genotoxicity of Alkylating Agents.

Wooder, Michael F. (1977) Molecular Interactions in the Assessment of the Genotoxicity of Alkylating Agents. Doctoral thesis, University of Surrey (United Kingdom)..

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The recognition and subsequent demonstration, in vitro, of the alkylating potential of dichlorvos has led to a suspicion that this triester of phosphoric acid may be a mutagen and a carcinogen. Despite consistently negative results obtained in mammalian mutagenicity and carcinogenicity tests it was never-the-less important to investigate the alkylating reactivity in vivo. In the experiments described in this thesis, male CFE rats were exposed to atmospheres containing 0,064ug 1[-1] of [Me-[14]C] dichlorvos (113Ci.mol[-1]) for 12 hours. Analysis of the DNA from the total soft tissues from 20 rats revealed no methylation at the N-7 atom of guanine moieties. A comparative study with [methyl-[14]C]methanesulphonate gave rise to a readily detectable extent of methylation of the N-7 atom of the guanine moieties in DNA. The limit of detection of methylation of the DNA in the dichlorvos study was one methyl group per 5.7 x 10[11] nucleotide units. The proportion of the administered dose that would be consumed in this hypothetical reaction would be 0.000001%. The exposure period employed in this study (12h) constituted a significant fraction of the half-live of 7-methylguanine moieties in DNA (3 days) and the current findings therefore indicate that dichlorvos would not methylate the DNA of mammalian tissues even when it is inhaled continuously for protracted periods of The administration of radiolabelled adenine, guanine, methionine and formate to otherwise untreated rats, gave rise to the excretion of radiolabelled methylated purines in urine. This finding indicates that the detection of radio- labelled methylated purines, per se, in the urine of animals exposed to methyl-labelled methylating agents does not constitute evidence for the spontaneous methylation of the purine moieties of nucleosides and nucleic acids by methylating agents, in vivo.

Item Type: Thesis (Doctoral)
Divisions : Theses
Authors :
Wooder, Michael F.
Date : 1977
Contributors :
Additional Information : Thesis (Ph.D.)--University of Surrey (United Kingdom), 1977.
Depositing User : EPrints Services
Date Deposited : 22 Jun 2018 15:17
Last Modified : 06 Nov 2018 16:54

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