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Immunological and toxicological studies on the benzopyrones

Lacy, Aoife (2004) Immunological and toxicological studies on the benzopyrones. PhD thesis, Dublin City University.

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Abstract

The Benzopyrones are a group of compounds whose members include coumarins (e.g. esculetin, warfarin) and flavonoids (e.g. genistein). An anti-warfarin monoclonal antibody (mAb) was successfully used to develop assays for the detection of warfarin in biological matrices. Warfarin was reproducibly detected in PBS and urine utilising both the enzyme-linked immunosorbent assay (ELISA) technique and BIAcore, a biosensing instrument. Cross reactivity studies illustrated that accnocoumarin exhibited the highest degree of cross reactivity with the anti-warfarin mAb, as expected, due to its high degree of structural similarity to warfarin. Coumarin displayed negligible cross reactivity due to its low degree of structural similarity to warfarin. Kinetic studies of mAb preparations yielded both dissociation constant (Kd) and association constant (Ka) values for warfarin and three structurally similar analogues. The mAb was successfully characterised. Toxicological effects of four benzopyrone compounds were investigated on two carcinoma cell-lines (A549 and MCF-7). Three different types of 96-well microtitre assays determined that genistein and esculetin respectively, were the most potent inhibitors of cell proliferation and metabolism. These results were compared to the results from the Cytosensor microphysiometer, a biosensor that detects cellular metabolism. Genistein was the most potent inhibitor on cellular metabolism followed by esculetin. In all assays both warfarin and 7-hydroxycoumarin showed weak inhibition of proliferation and metabolism. Other studies performed, illustrated the ability of genistein and esculetin to inhibit cell proliferation by DNA synthesis suppression. Studies on tyrosine kinase activity in MCF-7 cells suggest that esculetin and warfarin may suppress tyrosine kinase activity, which in turn has an inhibitory effect on cell proliferation. Overall, the potency of growth and metabolic inhibition by genistein was greater than esculetin, which was far greater than warfarin.

Item Type:Thesis (PhD)
Date of Award:2004
Refereed:No
Supervisor(s):O'Kennedy, Richard
Uncontrolled Keywords:Benzopyrones; Toxicology; Anti-warfarin monoclonal antibody
Subjects:Biological Sciences > Biotechnology
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health > School of Biotechnology
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 License. View License
ID Code:19166
Deposited On:23 Aug 2013 15:23 by Celine Campbell. Last Modified 23 Aug 2013 15:23

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