Open Daily: 10am - 10pm | Alley door pickup 10am - 7pm 3038 Hennepin Ave Minneapolis, MN
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  • Open Daily: 10am - 10pm
    Alley-side Pickup: 10am - 7pm

    3038 Hennepin Ave Minneapolis, MN
    612-822-4611

Open Daily: 10am - 10pm | Alley-side Pickup: 10am - 7pm
3038 Hennepin Ave Minneapolis, MN
612-822-4611
Liquid Chromatography-Mass Spectrometry for Detection and Characterization of DNA Biomarkers and Reactive Metabolites.

Liquid Chromatography-Mass Spectrometry for Detection and Characterization of DNA Biomarkers and Reactive Metabolites.

Argoti, Dayana

Paperback

Chemistry

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ISBN10: 1243528923
ISBN13: 9781243528926
Publisher: Proquest Umi Dissertation Pub
Pages: 172
Weight: 0.78
Height: 0.45 Width: 7.99 Depth: 10.00
Language: English
This dissertation presents advances in liquid chromatography-mass spectrometry for the analysis of reactive metabolites, DNA adducts and the evaluation of adult stem cell mechanisms. Chapter 1 provides an introduction to mass spectrometry, including electrospray, triple quadrupole and three-dimensional ion trap mass analyzers. In addition, human drug metabolism and specific metabolic processes relevant to the work presented in this dissertation are discussed. Chapter 2 deals with idiosyncratic or adverse drug reactions that are typically not detected until a large population has been studied, mostly during or after phase III clinical trials. Methods have been introduced in the pre-clinical phase of drug development to help identify compounds from a large library that form reactive metabolites. A commonly used technique for this purpose is glutathione (GSH) trapping assay, however, this assay only detects reactive metabolites that form stable GSH adducts. A high throughput LC-MS/MS method for the detection and characterization of iminium ion reactive intermediates via constant neutral loss of 27 in potassium cyanide microsomal incubations is presented. The method shows complementarity to GSH trapping results and provides preliminary structural information on detected cyano-adducts. Reported is a comprehensive triple quadrupole mass spectrometric investigation on the formation of cyanide adducts on a total of fourteen compounds. Chapter 3 describes the development of a multidimensional chromatography-mass spectrometric method for the quantification of DNA adducts of cigarette smoke constituent, 4-aminobiphenyl (4-ABP) in human bladder RT-4 cells. The method presented in this chapter represents an important improvement on the current methodologies for the analysis of 4-ABP-DNA adducts. The methodology was successfully applied to the evaluation of chemopreventive agents for the modulation of 4-ABP DNA adduct: N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dG-C8-ABP). Chapter 4 presents the utilization of LC-MS/MS to corroborate the theory of immortal DNA strands in adult stem cells (ASCs). Immortal DNA strands in ASCs were tagged with stable labeled thymidine, 15N-dT, and allowed to replicate for approximately eight generations. The amount of 15N-dT in immortal DNA strands was measured as a means to evaluate the degree of geometric label dilution. Chapter 5 provides insights for further improvements on the methodology presented in the previous chapters. In addition, suggestions for future research opportunities are discussed.

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