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Biomarkers of Exposure to Nitrosation Products of Amino Acids and Peptides

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Biomarkers of Exposure to Nitrosation Products of Amino Acids and Peptides Biomarkers of exposure to nitrosation products of amino acids and peptides. Thesis submitted for the degree of Doctor of Philosophy at the University of Leicester by Kathryn Lisa Harrison BSc. MSc. CMHT University of Leicester July 1998 UMI Number: U536777 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U536777 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract Biomarkers of exposure to nitrosation products of amino acids and peptides. Kathryn L. Harrison. The endogenous nitrosation of dietary amino acids and peptides may be a major source of genotoxic damage in the stomach and lower GI tract. Amongst the many N-alkyl-N- nitrosocompounds and related compounds, there are a number which share the common features of being derived from glycine and are carboxymethylating agents. Novel immunoaffinity-RP-HPLC-fluorescence methods were developed allowing the concomitant detection of 0 6-carboxymethy 1-2 ’ -deoxyguanosine (0 6-CMdG) and 0 6-methyl- 2’-deoxyguanosine (0 6-MedG) with limits of detection of 0.128pmol 0 6-CMdG/mol dG and 0.064(j.mol 0 6-MedG/mol dG in lmg of DNA. N-(N’-acetyl-L-prolyl)-N-nitrosoglycine (APNG), azaserine and potassium diazoacetate (KDA) all reacted with calf thymus DNA in vitro to give the expected 0 6-CMdG as well as lesser amounts of 0 6-MedG. The ratios of O6- MedGto 0 6-CMdG were 1:9.73 (APNG), 1:16.12 (KDA) and 1:38.45 (azaserine). However, these nitrosated glycine derivatives showed large differences in their capacity to alkylate DNA with 0 6-alkylation formation ratios of 1:12.1:137.9 for 5mM azaserine, APNG and KDA respectively. As 0 6-CMdG is not repaired by 0 6-alkylguanine alkyl transferases and is likely to be persistent in mammalian tissues, a sensitive immunoslotblot assay (0.32{imol 0 6-CMdG/mol dG) which required only lpg DNA for 0 6-CMdG was developed. 0 6-CMdG was detected in the stomach DNA of experimental animals treated with KDA or APNG by gastric intubation. Interestingly, control animals and non-target tissues of treated animals (liver, intestine) also had detectable levels of 0 6-CMdG. Examination of the DNA from human gastric biopsies from 30 individuals involved in a H. pylori study, revealed detectable amounts of 0 6-CMdG in 27 samples ranging from 0.60- 19.79pmol/mol dG. No statistically significant difference was found between individuals with or without H. pylori infection on the basis of 0 6-CMdG levels, although the highest levels observed were all in infected individuals. 0 6-CMdG was also detected in human white blood cell DNA from the H. pylori and a diet study with levels ranging from 0.66-15.42jj.mol/mol dG. 1 Contents ABSTRACT 1 CONTENTS 2 INDEX OF TABLES AND FIGURES. 9 ACKNOWLEDGMENTS 15 ABBREVIATIONS 16 CHAPTER 1. INTRODUCTION 19 1. Introduction. 20 1.1. Chemical carcinogenesis. 21 1.1.1. Historical perspective. 21 1.1.2. Chemical carcinogens: structure and activity. 22 1.1.3.Carcinogenesis is a multistage process. 23 1.1.3.1. Initiation and promotion. 24 1.1.3.2. Progression 25 1.1.4. Critical DNA targets during carcinogenesis. 26 1.1.4.1. Proto-oncogenes. 26 1.1.4.2. Tumour-suppressor genes. 27 1.1.4.3. Multiple genetic events occur during multistage carcinogenesis. 28 1.2. Alkylating Agents. 29 1.2.1. Biological consequences of alkylating exposure. 29 1.2.1.1. DNA Modification. 29 1.2.1.2. DNA Repair of Alkylated Bases 32 1.2.1.3. Non-random DNA alkylation and repair. 33 1.2.2. Human exposure to alkylating agents. 34 1.2.3. Use of Carcinogen-DNA Adducts as Biomarkers for Cancer. 35 2 Contents 1.3. Gastric Cancer. 38 1.3.1. Risk factors for Gastric Cancer. 3 8 1.3.2. Endogenous nitrosation. 39 1.3.2.1. Acid-catalysed endogenous nitrosation and its possible role in gastric cancer. 40 1.3.2.2. Bacterially mediated endogenous nitrosation and its possible role in gastric cancer. 41 1.3.3. The Correa model of gastric carcinogenesis. 42 1.3.3.1. Conditions with achlorhydria. 43 1.3.3.2. Helicobacter pylori and the importance of inflammation. 44 1.3.4. Measurements of N-nitroso compounds in gastric juice. 45 1.3.5. Precursors for endogenous nitrosation in the diet. 46 1.3.5.1. Amino acids and peptide nitrosation. 47 1.4. Biological activity of nitrosated peptides and compounds of related structure. 49 1.4.1. DNA alkylation adducts from nitrosated peptides and compounds of related structure. 50 1.4.2. Nitrosated glycine derivatives cause methylation as well as carboxymethylation of DNA. 52 1.4.3. The 0 6-carboxymethyldeoxyguanosine DNA adduct. 52 1.4.4. The 0 6-methyldeoxyguanosine DNA adduct. 53 1.4.5. Techniques available for the detection of DNA alkylation. 55 1.5. Aims of project. 57 CHAPTER 2. METHOD DEVELOPMENT 59 2.1. Introduction. 60 2.2. Synthesis of tritiated purine deoxynucleoside adducts. 61 2.3. 0 6-CMdG rabbit antiserum. 63 2.4. 0*-CMdG immunoaffinity column characterisation. 64 2.5. 0 6-MedG immunoaffinity column characterisation. 66 3 Contents 2.6. Preparation of N2-amino-S6-(carboxymethyl)-mercaptopurine for use as an Internal Standard. 68 2.7. HPLC optimisation for 0 6-alkylguanine adducts. 72 2.8. Digestion of DNA to nucleosides. 75 2.9. Sample preparation prior to HPLC analysis. 79 2.9.1. 0 6-CMdG immunoaffinity eluate 79 2.9.2. 0 6-MedG immunoaffinity eluate 80 2.10. Method validation 80 2.11. Discussion. 87 CHAPTER 3. IN VITRO STUDIES. 90 3.1. Introduction. 91 3.2. Concomitant formation of 0 6-CMdG and 0 6-MedG by N-carboxymethyl-N- nitrosocompounds and diazoacetic acid derivatives. 92 3.2.1. Analysis of 0 6-CMG and 0 6-MeG in DNA. 92 3.2.2. 0 6-alkylation by nitrosated glycine derivatives. 93 3.3. Mechanistic studies on 0 6-alkylation. 97 3.4. Discussion. 99 CHAPTER 4. IN VIVO ANIMAL STUDIES. 104 4.1. Introduction. 105 4.2. Development of the immunoslot blot assay for 0 6-CMdG. 107 4.3. In vivo APNG study. 110 4.4. In vivo KDA study. 112 4.4.1. Non-target tissue levels of 0 6-CMdG 4 hours after dosing with KDA. 112 4 Contents 4.4.2. Target tissue levels of 0 6-CMdG 4 hours and 24 hours after dosing with KDA. 114 . 4.5. Comparison of the immunoslot blot with the immunoafflnity-HPLC- fluorescence assay. 116 4.6. Discussion. 118 CHAPTER 5. HUMAN STUDIES. 123 5.1. Introduction. 124 5.2. H. pylori study. 125 5.2.1. 0 6-CMdG levels in gastric mucosa DNA. 125 5.2.2. 0 6-CMdG levels in white blood cell DNA. 129 5.3. Diet Study. 130 5.4. Discussion. 134 CHAPTER 6. DISCUSSION. 139 6.1 Discussion. 140 CHAPTER 7. MATERIALS AND METHODS 145 7.1. Materials and Methods for Chapter 2. 146 7.1.1. Apparatus. 146 7.1.2. Synthesis of tritiated purine deoxynucleoside derivatives. 146 7.1.2.1. Chemicals. 146 7.1.2.2. HPLC Systems. 146 7.1.2.3. Enzymatic Coupling. 147 7.1.2.3.1.Trial reaction: Chapeau & Mamett 147 7.1.2.3.2.Trial reaction: Stadler et al (1994) 147 7.1.2.3.3. [3H]-deoxyguanosine derivative synthesis. 148 7.1.2.4. Purification of [3H]-deoxynucleoside derivatives. 149 7.1.2.5. Quantitation of [3H]-deoxynucleoside derivatives. 150 5 Contents 7.1.3. Characterisation of rabbit 0 6-CMdG anti-serum. 152 7.1.4. Preparation and characterisation of immunoaffinity columns for 0 6-CMdG. 154 7.1.4.1. Materials and chemicals. 154 7.1.4.2. Preparation of columns 154 7.1.4.3. Characterisation of immunoaffinity columns for 0 6-CMdG. 155 7.1.4.4. Capacity determination for 0 6-CMdG immunoaffinity columns. 155 7.1.5. Preparation and characterisation of immunoaffinity columns for 0 6-MedG. 155 7.1.5.1. Materials and chemicals. 155 7.1.5.2. Preparation of columns. 156 7.1.5.3. Characterisation of immunoaffinity columns for 0 6-MedG. 156 7.1.5.4. Capacity determination for 0 6-MedG immunoaffinity columns. 156 7.1.6. Immunoaffinity work for S6-CMdG. 157 7.1.6.1. Binding and elution of [3H]-S6-CMdG using 0 6-CMdG immunoaffinity columns. 157 7.1.6.2. Determination of 0 6-CMdG column capacity for Oe-CMdG using [3H]- S6-CMdG as the marker compound. 157 7.1.6.3. Determination of binding of [3H]- S6-CMdG to the 0 6-CMdG columns in the presence of DNA digests. 157 7.1.7. HPLC optimisation for 0 6-alkylguanine adducts. 158 7.1.7.1. 0 6-CMG 158 7.1.7.2. 0 6-MeG 158 7.1.8. DNA digestion to nucleosides. 159 7.1.8.1. Chemicals. 159 7.1.8.2. Enzymatic digestion of DNA.
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