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Title: The identification and analysis of DNA damage by 1,3-butadiene epoxides
Author: Leuratti, C.
Awarding Body: University College of Swansea
Current Institution: Swansea University
Date of Award: 1993
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Epoxybutene (EB) and diepoxybutane (DEB) are metabolites of 1,3-butadiene (BUT), a carcinogen. They both react with DNA to form monoadducts, while DEB can also form crosslinks. Here, studies on DNA adducts formed by EB and DEB are presented. The aims were to develop methods for monitoring human exposure to BUT and to assist mechanistic studies on BUT-induced carcinogenesis. EB and DEB were reacted with deoxynucleosides, deoxynucleotides, polydeoxynucleotides and calf thymus DNA. The major product of the reaction of EB with dGMP was a 7N(1-hydroxy-3-buten-yl) dGMP. The N7-guanine base was previously synthesised and characterised by MS. Two N7-EB-guanines were detected by HPLC after depurination of treated DNA from human lymphocytes exposed in vitro. The synthetic N7-EB-dGMP was postlabelled and analysed. The low labelling efficiency limits its use as a marker of BUT exposure if 32P-postlabelling is used. HPLC analysis of DEB-dNps and polydNps identified an adenine (DEB-dAMP) and several guanine (DEB-dGMPs) adducts. A HPLC/postlabelling procedure for the detection of DEB-dAMP was developed and the adduct detected in poly(dA-dT) (dA-dT), calf thymus DNA and DEB treated CHO cells. The stability, the amount and the labelling efficiency of this adduct suggest it could be a suitable indicator of BUT exposure. Preliminary MS analysis of the corresponding nucleoside indicates an adenine adducted at the N6-position. Modified guanines corresponding to synthetic standards were detected in poly(dG-dC) (dG-dC). Synthetic DEB-dGMPs were postlabelled and conditions for their TLC separation established.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available