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Title: Genotoxicity of tamoxifen and structural analogues of tamoxifen : studies on the activation of tamoxifen by cytochrome P450s and peroxidase
Author: Davies, Adrian M.
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 1999
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This thesis investigates the activation of tamoxifen and structural analogues of tamoxifen by cytochrome P450s and peroxidase. In human lymphoblastoma derived cell lines expressing cDNAs for different human CYP-isoforms, tamoxifen, toremifene and 4-hydroxytamoxifen were clastogenic. Micronucleus formation was dependent on the dose of drug used and was not seen in cell lines not expressing these CYP isoenzymes. Results showed that CYP3A4 was the most important mono-oxygenase in the activation of these drugs. Clastogenicity was not detected when synthetic -hydroxytamoxifen or clomiphene were used. It was shown that in vitro, a horseradish peroxidase/H2O2 system could catalyse the N-demethylation and N-oxidation of tamoxifen and toremifene. Activation of [14C]tamoxifen or toremifene by this system was demonstrated by their irreversible binding to protein or to DNA. This reaction was catalysed by a number of peroxidases, including prostaglandin synthase. In the presence of DNA, activation of tamoxifen, 4-hydroxytamoxifen or toremifene resulted in the formation of 32P-postlabelled DNA adducts. 4-Hydroxytamoxifen was broken down by peroxidases much faster than tamoxifen. Reaction products, detected by HPLC-electrospray mass spectrometry, had structures consistent with 4-hydroxytamoxifen dimers. Incubation of 4-hydroxytamoxifen with horseradish peroxidase, H2O2, glutathione and the radical trap DMPO leads to the formation of a glutathione thiyl radical that can be detected with electron paramagnetic resonance spectrometry. The presence of the thiyl radical supports the proposal for the formation of a phenoxyl radical from 4-hydroxytamoxifen.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available