Bibliography: leaves 246-263. / xiii, 263 leaves : col. ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Previous investigations have established that there is a syndrome that occurs with abstinence from alcohol, and that it is characterised by certain signs and symptoms. This thesis aims to redress the paucity of information on symptom intensity and duration, predictors of withdrawal severity, and relationship of withdrawal severity to relapse. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 2000

published_or_final_version / abstract / Ecology and Biodiversity / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

The cytochrome P-450 dependent monooxygenase system plays a key role in the bioactivation and detoxication of xenobiotics. Isozyme-specific inhibitors of cytochrome P-450 may be useful in elucidating the role of particular isozymes in xenobiotic metabolism or in suppressing the bioactivation of xenobiotics and enhancing detoxication. The antibiotic chloramphenicol is a selective mechanism-based inactivator of rat liver cytochromes P-450, inactivating 6 of the 12 isozymes monitored, including the major phenobarbital-inducible isozyme PB-B. Analogs of chloramphenicol have been tested to determine the importance of various functional groups in regulating the effectiveness and isozyme selectivity of chloramphenicol as a mechanism-based inactivator of cytochromes P-450. This information will aid in the design of more effective and isozyme specific mechanism-based inactivators. The dihalomethyl group and the propanediol moiety were found to be important in determining the efficacy of inactivation and the ability to inactivate the enzyme by virtue of the modification of the protein as opposed to the modification of the heme moiety. The propanediol side chain also plays a role in the isozyme selectivity. Unlike chloramphenicol, N (2-p-nitrophenethyl)dichloroacetamide (pNO₂DCA), which contains an ethyl group in place of the propanediol side chain of chloramphenicol, is an effective inactivator of BNF-B, the major beta-naphthoflavone-inducible isozyme, as well as PB-B, in vitro and in vivo. Alkaline hydrolysis and enzymatic digestion of the covalently modified isozymes has shown that chloramphenicol and pNO₂DCA are both metabolized by cytochromes P-450 to oxamyl chlorides which bind to lysine and other amino acid residues of the enzyme. However, the mechanism by which pNO₂DCA inactivates BNF-B differs significantly from that by which chloramphenicol inactivates PB-B, although both involve an impairment of the transfer of electrons from NADPH-cytochrome P-450 reductase, suggesting that there are differences in the active sites of these two isozymes.

Experiments were conducted to examine the cause of lag-phase growth during phenol degradation by mixed microbial cultures that had been acclimated to one of four substrates. Four aerated Imhoff cones were inoculated with wastewater sludge and fed one of four substrates: acetate, egg albumin, vegetable oil, or phenol. Inocula from these cones were injected into batch reactors containing phenol. Time-dependent growth was measured by two methods: most probable number (MPN) and epifluorescence microscopy (EM). The MPN technique was used to distinguish two cell concentrations: total cells and a phenol-degrading community within the total; EM was also used to count total cells. The results indicated that a lag in phenol utilization for all cultures, except the phenol-acclimated cultures, was a result of growth of a phenol-degrading subpopulation, and not due to enzyme induction of the existing population. Similar experiments were conducted using 2,4-dichlorophenol (2,4-DCP), which resulted in no growth and no degradation of 2,4-DCP.

Insecticide resistance is a global problem. Insecticide resistance management is very important, considering the time, effort, and cost of discovering and developing a new insecticide. There are diverse resistance mechanisms, but enhanced detoxification through overexpression of cytochrome P450s and target site insensitivity through mutation in insecticide binding site are the two most common mechanisms. The xenobiotic detoxification is divided into three successive phases (I, II and III), which ensures the metabolism and excretion of the detrimental toxins. Each phase comprises of a specific group of metabolizing enzymes such as P450s (phase I), GSTs (phase II) and ABC transporters (phase III). The major goal of my research was to understand the molecular mechanism of insecticide resistance in two economically important coleopteran pests, Leptinotarsa decemlineata and Tribolium castaneum. The transcriptional regulation of the P450 genes mediating insecticide resistance in L. decemlineata (imidacloprid-resistant) and T. castaneum (deltamethrin-resistant) were studied and the xenobiotic trans and cis-elements identified. RNA interference (RNAi), and reporter assays revealed that the cytochrome P450 genes involved in insecticide resistance are regulated by transcription factor Cap n Collar ‘CncC’ and muscle aponeurosis fibromatosis ‘Maf’ belonging to the b-ZIP transcription factor family. Site-directed mutagenesis was employed to identify the binding site for CncC and Maf. Sequencing of RNA isolated from CncC knockdown T. castaneum identified genes regulated by CncC and involved in insecticide detoxification. RNAi and insecticide bioassays confirmed the function of select phase II (glutathione-S-transferases) and phase III (ABC transporters) identified by RNA sequencing. Overall, these data revealed that the xenobiotic transcription factor CncC is the master regulator of multiple genes that are involved in insecticide resistance.

Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 165-168). Also available online.

Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 165-168). Also available in print.

No description available.

Thesis (Ph. D.)--Joint Program in Oceanography/Applied Ocean Science and Engineering (Massachusetts Institute of Technology, Dept. of Biology; and the Woods Hole Oceanographic Institution), 2008. / Page 362 blank. / Includes bibliographical references. / Understanding how organisms deal with potentially toxic or fitness-reducing allelochemicals is important for understanding patterns of predation and herbivory in the marine environment. The ability of marine consumers to tolerate dietary toxins may involve biochemical resistance mechanisms, which increase the hydrophilicity of compounds and facilitate their active efflux out of sensitive cells and tissues. While several allelochemical-responsive detoxification enzymes have been sequenced and functionally characterized in terrestrial invertebrates feeding on chemically defended host plants, there is virtually no information concerning the role of these biotransformation enzymes that may mediate feeding tolerance in marine invertebrates. The objective of this research was to assess the diversity and dietary regulation of cytochrome P450s (CYP), glutathione S-transferases (GST) and ABC transporters in the generalist marine gastropod Cyphoma gibbosum feeding on a variety of chemically defended gorgonian corals, and to identify those dietary natural products that act as substrates for these proteins. Molecular and proteomic techniques identified both allelochemically-responsive CYPs, and constitutively expressed GSTs and transporters in Cyphoma digestive glands. Inhibition of Cyphoma GST activity by gorgonian extracts and selected allelochemicals (i.e., prostaglandins) indicated that gorgonian diets are likely to contain substrates for molluscan detoxification enzymes. In vitro metabolism studies with recombinant CYPs suggested those Cyphoma enzymes most closely related to vertebrate fatty acid hydroxylating enzymes may contribute to the detoxification ofichthyodeterrent cyclopentenone prostaglandins found in abundance in selected gorgonian species. / (cont.) Finally, the presence and activity of multixenobiotic resistance transporters in Cyphoma and the co-occurring specialist nudibranch, Tritonia hamnerorum, suggests these efflux transporters could function as a first line of defense against dietary intoxication. Together, these results suggest marine consumers that regularly exploit allelochemical-rich prey have evolved both general (GST and ABC transporters) and allelochemical-specific (CYP) detoxification mechanisms to tolerate prey chemical defenses. / by Kristen Elizabeth Whalen. / Ph.D.