Physical and chemical interactions between bile pigments and polyaromatic mutagens
➤ Gửi thông báo lỗi ⚠️ Báo cáo tài liệu vi phạmNội dung chi tiết: Physical and chemical interactions between bile pigments and polyaromatic mutagens
Physical and chemical interactions between bile pigments and polyaromatic mutagens
The University Of QueenslandAUSTRALIAPhysical and chemical interactions between bile pigmentsand polyaromatic mutagensHung Tricu HongBSc. and Master i Physical and chemical interactions between bile pigments and polyaromatic mutagens in Organic ChemistryA thesis submitted for the degree of Doctor of Philosophy arThe University of Queensland in 2015School of Chemistry and Molecular BiosciencesAbstractA major cause of cancer in humans is exposure to mutagenic compounds. This raises the question of how humans can be protected from Physical and chemical interactions between bile pigments and polyaromatic mutagens these environmental mutagens. Bile pigments (Bps) such as biliverdin, unconjugated bilirubin and protoporphyrin and their derivatives have recently bePhysical and chemical interactions between bile pigments and polyaromatic mutagens
en found to act as antioxidants and inhibit the mutagenic effects of several known environmental mutagens including 2-aminofluorene. benzo[a]pyrene, aThe University Of QueenslandAUSTRALIAPhysical and chemical interactions between bile pigmentsand polyaromatic mutagensHung Tricu HongBSc. and Master i Physical and chemical interactions between bile pigments and polyaromatic mutagens is achieved. Understanding these mechanisms would be useful for future drug development. Therefore, this PhD thesis aims to explore physical and chemical interactions between BPs and mutagens. Effects of BPs on the bioavailability and metabolism of mutagens were also examined in vitro using the colo Physical and chemical interactions between bile pigments and polyaromatic mutagens rectal adenocarcinoma (Caco-2 cell) monolayer model and the human liver S9 fraction.1 he physical interactions between mutagens and BPs were examinedPhysical and chemical interactions between bile pigments and polyaromatic mutagens
using three different methods: NMR. uv and effects of bioavailability. The results of the comparison of the NMR spectra of mutagens in the absence andThe University Of QueenslandAUSTRALIAPhysical and chemical interactions between bile pigmentsand polyaromatic mutagensHung Tricu HongBSc. and Master i Physical and chemical interactions between bile pigments and polyaromatic mutagens tions between the BPs and mutagens. The uv spectrum of each mutagen was measured in the presence and absence of varying concentrations of BPs. and there were no changes to the uv spectra of any of the compounds. Strong physical interactions or aggregation of compounds can also affect their absorptio Physical and chemical interactions between bile pigments and polyaromatic mutagens n across cell monolayers and so the apparent permeability of mutagens across Caeo-2 cell monolayers in the presence and absence of BPs were measured.Physical and chemical interactions between bile pigments and polyaromatic mutagens
The results indicated that BPs increased the permeability of the mutagens slightly and effected how much of the compounds remained in tight associatioThe University Of QueenslandAUSTRALIAPhysical and chemical interactions between bile pigmentsand polyaromatic mutagensHung Tricu HongBSc. and Master i Physical and chemical interactions between bile pigments and polyaromatic mutagens ly to be a major contributing mechanism of the inhibitory effects of BPs on environmental mutagens.Chemical reactions between BPs and the DNA modifying metabolites of mutagens (epoxides) were smdied using styrene epoxide as a model for the reactive metabolites. Styrene epoxide is commercially availa Physical and chemical interactions between bile pigments and polyaromatic mutagens ble, stable and less toxic than the reactive metabolites of the mutagens. Competitive reactions were performed in which BPs and their derivatives werePhysical and chemical interactions between bile pigments and polyaromatic mutagens
placed in solution with guanine and allowed to react with styrene epoxide. These reactions showed that BPs and their dimethyl esters are more reactivThe University Of QueenslandAUSTRALIAPhysical and chemical interactions between bile pigmentsand polyaromatic mutagensHung Tricu HongBSc. and Master i Physical and chemical interactions between bile pigments and polyaromatic mutagens he major products isolated form the reactions. The pyrrole rings in bilirubin also showed some evidence ofiireaction with styrene epoxide though the products were too unstable to isolate. Thus, it was clear that BPs can effectively scavenge reactive metabolites, but the free carboxylic acids were si Physical and chemical interactions between bile pigments and polyaromatic mutagens gnificantly more effective at this than the dimethyl ester derivatives. This is not reflected in the anti-mutagenic activities of the compounds. Also,Physical and chemical interactions between bile pigments and polyaromatic mutagens
the ubiquitous nature of carboxylic acid groups in the cellular environment makes it unlikely that this reaction with activated epoxides would be uniThe University Of QueenslandAUSTRALIAPhysical and chemical interactions between bile pigmentsand polyaromatic mutagensHung Tricu HongBSc. and Master i Physical and chemical interactions between bile pigments and polyaromatic mutagens the inhibition of BPs.Another possible mechanism of action of the BPs is that they inhibit the formation of the DNA modifying metabolites of the mutagens. We investigated this by performing in vitro experiments in which mutagens were co-incubalcd in the human liver S9 fraction in the presence and a Physical and chemical interactions between bile pigments and polyaromatic mutagens bsence of BPs. The results indicated BPs were inhibitors of the metabolism of benzo|ajpyrene and 2-amino-l-mcthyl-6-phcnylimidol4.5-blpyridinc by livePhysical and chemical interactions between bile pigments and polyaromatic mutagens
r enzymes, lhe order of inhibitory effectiveness was bilirubin > protoporphyrin > biliverdin. Molecular modelling studies which examined the docking oThe University Of QueenslandAUSTRALIAPhysical and chemical interactions between bile pigmentsand polyaromatic mutagensHung Tricu HongBSc. and Master i Physical and chemical interactions between bile pigments and polyaromatic mutagens ggested BPs could bind to the active sites of CYP1A1, 1A2. 1B1 and 3A4.hl summary, we conducted a scries of experiments to evaluate the likely mechanisms of the inhibitory effects of BPs on known environmental mutagens. There arc several theories postulated to explain the anti-mutagenic effects of B Physical and chemical interactions between bile pigments and polyaromatic mutagens Ps including the physical Tt-stacking driven aggregation of BPs with the polyaromatic mutagens, the chemical scavenging of BPs towards reactive metaboPhysical and chemical interactions between bile pigments and polyaromatic mutagens
lites, and the inhibition of BPs of the P450 mediated activation of the mutagens. We have systematically tested each of these and found that the latteThe University Of QueenslandAUSTRALIAPhysical and chemical interactions between bile pigmentsand polyaromatic mutagensHung Tricu HongBSc. and Master i Physical and chemical interactions between bile pigments and polyaromatic mutagens utagenesis and thus may lead to the development of synthetic compounds that could decrease the risk to humans exposed to these environmental mutagens.iiiDeclaration by authorThis thesis is composed of my original work, and contains no material previously published or written by another person except Physical and chemical interactions between bile pigments and polyaromatic mutagens where due reference has been made in the text. 1 have clearly stated the contribution by others to jointly-authored works that I have included in myPhysical and chemical interactions between bile pigments and polyaromatic mutagens
thesis.I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, signiThe University Of QueenslandAUSTRALIAPhysical and chemical interactions between bile pigmentsand polyaromatic mutagensHung Tricu HongBSc. and Master i Physical and chemical interactions between bile pigments and polyaromatic mutagens is is (he result of work 1 have carried out since the commencement of my research higher degree candidature and does not include a substantial pait of work that has been submitted to quality for the award of any other degree or diploma in any university or other tertiary institution. I have clearly Physical and chemical interactions between bile pigments and polyaromatic mutagens stated which parts of my thesis, if any. have been submitted to quality' for another award.1 acknowledge that an electronic copy of my thesis must bePhysical and chemical interactions between bile pigments and polyaromatic mutagens
lodged with the University Library and. subject to the policy and procedures of The University of Queensland, the thesis be made available for researcThe University Of QueenslandAUSTRALIAPhysical and chemical interactions between bile pigmentsand polyaromatic mutagensHung Tricu HongBSc. and Master i Physical and chemical interactions between bile pigments and polyaromatic mutagens at copyright of all material contained in my thesis resides with the copyright holdcr(s) of that material. Where appropriate 1 have obtained copyright permission from the copyright holder to reproduce material in this thesis.ivPublications during candidaturePeer Reviewed Papers:Molzcr. c.; Huber. H. Physical and chemical interactions between bile pigments and polyaromatic mutagens ; Steyrer, A.; Ziesel, G. V.; Wallner. M.; Hong, 11. T.; Blanchfield. J. T.; Bulmer. A. c.: Wagner. K. H.. Bilirubin and related tetrapyrroles inhibitPhysical and chemical interactions between bile pigments and polyaromatic mutagens
food-borne mutagenesis: A mechanism for antigenotoxic action against a model epoxide. J. Nat. Prod. 2013. 76 (10). 1958-1965.Manuscripts to be submitThe University Of QueenslandAUSTRALIAPhysical and chemical interactions between bile pigmentsand polyaromatic mutagensHung Tricu HongBSc. and Master i Physical and chemical interactions between bile pigments and polyaromatic mutagens s of endogenous bile pigments on 2-Amino-l-methyl-6-phenylimidazo[4.5-blpyridinc and BenzofalPyrcuc metabolic activation by cytochrome P-150 enzymes. Drug Metab. Dispos. 2015.Hong H. T.. Bulmer. A. c.. Wagner. K. H.. De Voss. James J., Blanchfield. J. T. investigation into the physical interactions Physical and chemical interactions between bile pigments and polyaromatic mutagens between 2-Amino-l-mcthyl-6-phcnylimidazo(4.5-b)pyridinc and bile pigments. J. Appt. Toxicol. 2015.Hong u. 1.. Bulmer. A. c., Wagner. K. 11.. De Voss.Physical and chemical interactions between bile pigments and polyaromatic mutagens
James J.. Blanchlicld. J. r. Preliminary examinations into the mechanism of reactions that may contribute to the inhibition of mutagenic epoxide agentThe University Of QueenslandAUSTRALIAPhysical and chemical interactions between bile pigmentsand polyaromatic mutagensHung Tricu HongBSc. and Master i Physical and chemical interactions between bile pigments and polyaromatic mutagens 1. J., Blanchfield. J. T.. The evaluation of physical and chemical interactions between bite pigments and polyaromatic mutagens, 8th Annual Research Students Symposium School of Chemistry and Molecular Biosciences. The University of Queensland. Australia. November 2012. Abstract and poster presentat Physical and chemical interactions between bile pigments and polyaromatic mutagens ion.Hung, H. T.; Wagner, K.H.; Bulmer. A.c. De Voss. J. J., Blanchfield. J. T-, Mechanistic evaluation of chemical interactions between dipyrroles, tePhysical and chemical interactions between bile pigments and polyaromatic mutagens
trapyrroles and polyaromatic mutagens. 9th Annual Research Students Symposium School of Chemistry and Molecular Biosciences, The University of QueenslGọi ngay
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