Thesis (M.Sc. (Pharmacology))--Mahidol University, 1976.

by Leung Yuet Kin. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 86-100). / Abstract also in Chinese. / List of Figures --- p.ix / List of Tables --- p.xii / List of Abbreviations --- p.xiii / Chapter Chapter One: --- Introduction / Chapter 1.1 --- Carcinogenicity of the tobacco products --- p.1 / Chapter 1.2 --- Biochemical Pathway involved in NNK metabolism --- p.5 / Chapter 1.2.1 --- Metabolic activation of NNK --- p.6 / Chapter 1.2.2 --- Detoxification of NNK --- p.8 / Chapter 1.3 --- Modulation of NNK carcinogenesis --- p.9 / Chapter 1.4 --- Mediation of NNK oxidation : chemoprevention by isothiocyanates --- p.11 / Chapter 1.5 --- Aim of study --- p.13 / Chapter 1.5.1 --- Experimental approaches --- p.15 / Chapter Chapter Two : --- Modulation of α-carbon hydroxylations in NNK metabolism / Chapter 2.1 --- Background --- p.17 / Chapter 2.2 --- Materials and Methods --- p.17 / Chapter 2.2.1 --- Chemicals --- p.17 / Chapter 2.2.2 --- Methods --- p.18 / Chapter 2.2.2.1 --- Preparation of rat microsomes --- p.18 / Chapter 2.2.2.2 --- Assay of NNK metabolism --- p.18 / Chapter 2.2.2.3 --- Determination of solvent extraction --- p.19 / Chapter 2.2.2.4 --- Determination of detergent effects --- p.19 / Chapter 2.2.2.5 --- HPLC analysis of NNK metabolites --- p.20 / Chapter 2.2.2.6 --- Study of strain differences between SD rats and F344 rats --- p.20 / Chapter 2.3 --- Results --- p.21 / Chapter 2.3.1 --- HPLC analysis of NNK metabolites --- p.21 / Chapter 2.3.2 --- Determination of solvent extraction --- p.22 / Chapter 2.3.3 --- Effects of detergents --- p.25 / Chapter 2.3.4 --- Study of strain differences using F344 rats and SD rats --- p.26 / Chapter 2.4 --- Discussion --- p.27 / Chapter Chapter Three : --- Modulation by potentiation of detoxification process in NNK metabolism / Chapter 3.1 --- Background --- p.30 / Chapter 3.2 --- Materials and Methods --- p.31 / Chapter 3.2.1 --- Chemicals --- p.31 / Chapter 3.2.2 --- Methods --- p.32 / Chapter 3.2.2.1 --- Preparation of rat microsomes --- p.32 / Chapter 3.2.2.2 --- Analysis of NNK metabolism --- p.32 / Chapter 3.2.2.3 --- UDP-glucuronosyltransferase Assay --- p.33 / Chapter 3.2.2.4 --- Cytochrome P450 2E1 Assay --- p.34 / Chapter 3.3 --- Results --- p.34 / Chapter 3.3.1 --- Screening tests of the effects of vitamins and drugs --- p.34 / Chapter 3.3.1.1 --- Male liver microsomes --- p.35 / Chapter 3.3.1.2 --- Female liver microsomes --- p.37 / Chapter 3.3.1.3 --- Male lung microsomes --- p.39 / Chapter 3.3.1.4 --- Female lung microsmes --- p.41 / Chapter 3.3.2 --- Kinetic analysis of vitamin C-palmitate on NNK reduction --- p.43 / Chapter 3.3.3 --- Effects of vitamin C-palmitate on UDP- glucuronosyltransferase --- p.47 / Chapter 3.3.4 --- Effects of vitamin C-palmitate on cytochrome P4502E1 (CYP2E1) --- p.48 / Chapter 3.4 --- Discussion --- p.50 / Chapter Chapter Four: --- Purification of carbonyl reductase from rat liver microsomes / Chapter 4.1 --- Background --- p.58 / Chapter 4.2 --- Materials and Methods --- p.58 / Chapter 4.2.1 --- Chemicals --- p.58 / Chapter 4.2.2 --- Methods --- p.59 / Chapter 4.2.2.1 --- Preparation of male rat liver microsomes --- p.59 / Chapter 4.2.2.2 --- Purification of carbonyl reductase from rat liver microsomes --- p.59 / Chapter A. --- Solubilization of microsomes --- p.59 / Chapter B. --- Chromatographic separation by octyl-Sepharose CL-4B --- p.60 / Chapter C. --- Chromatographic separation by DEAE-cellulose --- p.60 / Chapter 4.2.2.3 --- SDS polyacrylamide gel electrophoresis --- p.61 / Chapter 4.3 --- Results --- p.61 / Chapter 4.4 --- Discussion --- p.63 / Chapter Chapter Five : --- Summary and Discussion / Chapter 5.1 --- Summary --- p.66 / Chapter 5.2 --- Discussion --- p.67 / Chapter 5.2.1 --- Anticarcinogenesis of vitamin C in NNK-induced cancer through smoking --- p.67 / Chapter 5.2.2 --- Future studies on microsomal carbonyl reductase --- p.68 / Chapter 5.2.3 --- Future studies on UDP-glucuronidation of NNAL --- p.72 / Appendix A Effects of atropine on tolbutamide metabolism --- p.74 / Appendix B Recovery of keto acid and keto alcohol from the assay mixture ( without solvent extraction ) --- p.75 / Appendix C Calibration Curve of NNAL --- p.76 / Appendix D Effects of methanol on NNK carbonyl reduction --- p.77 / Appendix E Time course study of NNAL production at various concentrations of vitamin C-palmitate --- p.78 / Appendix F Time course assay of UDP-glucuronosyltransferase at various concentrations of vitamin C-palmitate --- p.80 / Appendix G Calculation of specific activity of UDP-Glucuronosyl transferase --- p.82 / Appendix H Calculation of specific activity of cytochrome P450 2E1 --- p.84 / References --- p.86

Thesis (Ph.D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Pharmaceutics. Title from title-page of electronic thesis. Bibliography: leaves 207-235.

No description available.

Nucleophiles react with the α-acetoxy derivative of α-hydroxybenzylbenzylnitrosamine at the carbonyl carbon of the acetoxy moiety followed by fragmentation to the very same intermediates formed by oxidative metabolism. Since α-acetoxybenzylbenzylnitrosamine has been shown to be able to acylate nucleophiles and since the nucleic acids are nucleophiles, then it is possible that this compound may cause mutations by an acylation pathway instead of or in addition to the more common alkylation pathway. The data in Part I of this dissertation should be considered in any further biological investigations of N,N-dialkylnitrosamine induced mutagenesis or carcinogenesis. The study of the synthesis, reactions, mutagenicity, and the possible correlation to compound liposolubility of cyclic N-nitrosamines was also investigated.

Although dialkylnitrosamines are environmentally significant carcinogens, the use of short-term bioassays to assess the mutagenic potential of these compounds remains problematic. The Ames test, a mutagenicity assay based on the reversion of Salmonella typhimurium histidine auxotrophs, is the most widely used bioassay in genetic toxicology, but the traditional Ames tester strains are largely insensitive to dialkylnitrosamine mutagenicity. I have constructed several mutagenicity tester strains that co-express combinations of full-length human cytochrome P450 2E1, rat cytochrome P450 reductase, and human cytochrome b5 in S. typhimurium lacking ogt and ada methyltransferases (YG7104ER, ogt-; and YG7108ER, ogt-, ada-). These new strains are susceptible to dialkylnitrosamine mutagenicity in the absence of an exogenous metabolic activating system (S9 fraction). Mutagenicity is dependent upon the coexpression of P450 2E1 with P450 reductase and is similar or greater than that obtained with the parental strains in the presence of S9 fraction from ethanol-induced rat liver. Coexpressing human cytochrome b5 with cytochrome P450 2E1 and cytochrome P450 reductase potentiates the mutagenicity observed with dialkylnitrosamines. These strains were sensitive to nitrosamines with varying alkyl side chains, including dimethylnitrosamine, diethylnitrosamine, dipropylnitrosamine, and dibutylnitrosamine. Mutagenicity decreased with alkyl chain length, consistent with the stringency of the ada-encoded enzyme for methyl and ethyl DNA adducts. These new strains may prove useful in the evaluation of nitrosamine contamination of food and environmental samples, and may serve as useful tools in investigating the molecular properties of proteins in the cytochrome P450 monooxygenase system.

N-Nitrosodimethylamine (NDMA), which is a carcinogenic and toxic N-nitrosamine, can be found in water resources associated with a multitude of processes in various industrial facilities or merely as a by-product of water or wastewater treatment. Therefore, the removal of NDMA from drinking water represents an important human safety and public health concern. The present paper presents a density functional theory study of NDMA adsorption in all-silica MFI, Na-ZSM-5 and H-ZSM-5 zeolites. The stability of NDMA inside the zeolite pores was investigated by calculating the amount of energy released during adsorption. Various configurations of adsorbed NDMA to the zeolites were investigated, predominantly at the intersection of straight and sinusoidal channels. The strength of the adsorption energies followed the order H-ZSM5 > Na-ZSM-5 > all-silica MFI. NDMA has a dipole moment and the strongest binding of NDMA occurred through the interactions of the negatively charged O atom of the molecule to positive atoms of the zeolite. Similar calculations were performed for water adsorption in these three zeolites. The adsorption energy of water to these three structures followed the order Na-ZSM5 > H-ZSM-5 > all-silica MFI. We also incorporated van der Waals corrections in the simulations, which had the effect of stabilizing NDMA within the zeolite channels, but did not significantly change the relative stability of the different adsorption geometries. It was concluded that H-ZSM-5 is the best choice to remove NDMA because it is strong enough to adsorb NDMA and it is not too strong in adsorption of water molecules.

Ultraviolet direct photolysis (UV) and the advanced oxidation process UV/H2O2 are new technologies in the water treatment industry. Both treatments can cause the transformation of organic compounds. Nitrosamines and organic chloramines are disinfection by-products (DBPs) formed from the reaction of organic nitrogen compounds during chlorination or chloramination (chlor(am)ination) disinfection. It is therefore possible for UV and UV/H2O2 to affect the organic compound precursors for nitrosamines and organic chloramines and thus their formation from subsequent chlor(am)ination. The precursor compounds, UV and H2O2 doses used for UV or UV/H2O2, and alkalinity were found to have an effect on the formation of nitrosamines and organic chloramines during bench-scale experiments. Full scale studies found UV and UV/H2O2 had different effects on the formation of different nitrosamine species and organic chloramine concentrations, and that a potential correlation existed between the formation of organic chloramines from chlorination and the formation of N-nitrosodimethylamine from chloramination.

Ultraviolet direct photolysis (UV) and the advanced oxidation process UV/H2O2 are new technologies in the water treatment industry. Both treatments can cause the transformation of organic compounds. Nitrosamines and organic chloramines are disinfection by-products (DBPs) formed from the reaction of organic nitrogen compounds during chlorination or chloramination (chlor(am)ination) disinfection. It is therefore possible for UV and UV/H2O2 to affect the organic compound precursors for nitrosamines and organic chloramines and thus their formation from subsequent chlor(am)ination. The precursor compounds, UV and H2O2 doses used for UV or UV/H2O2, and alkalinity were found to have an effect on the formation of nitrosamines and organic chloramines during bench-scale experiments. Full scale studies found UV and UV/H2O2 had different effects on the formation of different nitrosamine species and organic chloramine concentrations, and that a potential correlation existed between the formation of organic chloramines from chlorination and the formation of N-nitrosodimethylamine from chloramination.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第22057号 / 工博第4638号 / 新制||工||1723(附属図書館) / 京都大学大学院工学研究科都市環境工学専攻 / (主査)教授 田中 宏明, 教授 伊藤 禎彦, 講師 中田 典秀 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM