by Ho Ka-Pong, Bosco. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1993. / Includes bibliographical references (leaves 81-100). / Chapter CHAPTER 1: --- INTRODUCTION --- p.1 / Chapter CHAPTER 2: --- PURIFICATION OF HUMAN CLASS I LIVER ADH --- p.19 / Chapter CHAPTER 3: --- DISSOCIATION AND REASSOCIATION OF HUMAN CLASS I ADH BY FREEZE/THAW TECHNIQUE --- p.36 / Chapter CHAPTER 4: --- "DISSOCIATION AND REASSOCIATION OF HUMAN CLASS I ADH BY USING UREA, GdmCl,HIGH SALT AND LOW pH" --- p.51 / Chapter CHAPTER 5: --- GENERAL DISCUSSION --- p.77 / REFERENCES --- p.81

by Fong Wing-ping. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1987. / Bibliography: leaves 186-198.

The metabolism of lignocaine to monoethylglycinexylidide has been found useful as an indicator of hepatic function in association with liver transplantation. It has been postulated that this might be due to the common effect of hypoxic damage on liver function and lignocaine metabolism. The aim of this work was to establish whether hepatic lignocaine elimination was impaired by hypoxia and whether lignocaine extraction ratio and clearance could be used as an indicator of hepatic function. This was studied using the isolated pig liver perfused via the hepatic artery and portal vein. To establish whether the pig liver could be used as a possible human model for this investigation and whether lignocaine had any detrimental effects on liver function and blood flow in vivo, hepatic lignocaine elimination and the effects of lignocaine administration on hepatic function and blood flow were studied in the anaesthetized pig, surgically prepared to allow sampling across the liver and direct hepatic blood flow measurement. Hepatic lignocaine elimination was then studied in the isolated perfused liver to determine whether this was similar to that found in vivo. The definitive studies required preliminary investigations not available from the literature to determine the feasibility of comparing in vivo and ex vivo hepatic function using the same liver. In addition, by studying the decay of lignocaine after bolus dose administration the necessary pharmacokinetic parameters to achieve similar constant hepatic affluent lignocaine concentrations in vivo and in the isolated preparation could be determined. The preliminary investigations showed that a sequential experiment using the same liver to compare in vivo and ex vivo function was inappropriate as the energy state of isolated perfused livers previously studied in vivo was significantly different from that in livers perfused immediately. The decay of lignocaine after a bolus dose in vivo and ex vivo could be described by a two-compartment open model and in both preparations the derived pharmacokinetic parameters from this analysis were used to achieve similar constant hepatic affluent concentrations over the study period used to determine hepatic lignocaine elimination. Lignocaine extraction ratio by the in situ pig liver was similar to that reported in man and together with hepatic clearance and intrinsic clearance was similar to that determined in the isolated state when different livers were used for this comparison. There was no detrimental effect of lignocaine administration on hepatic function and blood flow In vivo. Lignocaine extraction ratio and clearance and monoethylglycinexylidide formation were significantly impaired in livers subjected to hypoxia. Lignocaine elimination correlated strongly with hepatic cellular ATP, energy charge and ATP/ ADP ratio as well as with hepatic potassium release but less strongly with aspartate aminotransferase release when this relationship was tested using the combined data from hypoxic and normoxic livers ex vivo. These correlations were positive for hepatic adenine nucleotide status and negative for hepatic potassium and aspartate aminotransferase release. Neither hepatic alanine aminotransferase release nor lactate utilization were significantly affected by hypoxia. Lignocaine extraction ratio, hepatic oxygen consumption, ATP content, bile flow and potassium release were shown to be equivalent, more highly sensitive, and earlier indicators of hypoxic hepatic injury than hepatic aspartate aminotransferase release in the isolated perfused pig liver.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in partial fulfillment of the requirements for the degree of Master of Science in Medicine in Pharmacotherapy, Johannesburg, 2011 / Long term antiretroviral therapy (ART) use is known to cause various toxic adverse effects in patients. Hepato-toxicity is one of the most significant adverse effects which have been associated with all antiretroviral therapy drugs in South Africa and worldwide.

lsoflurane interacts with cytochrome P-450 in rat and human hepatic microsomes and the Δ6- and Δ5-desaturases in rat hepatic microsomes. The interaction of isoflurane with cytochrome P-450 results in its metabolism to fluoride ion and organofluorine metabolites. The cytochrome P-450 isozymes catalysing the defluorination of isoflurane were assessed in hepatic microsomes from phenobarbital-, β-naphthoflavone- and pregnenolone-16α-carbonitrilepretreated and untreated rats. One or more of the cytochrome P-450 isozymes induced by phenobarbital and pregnenolone-16α-carbonitrile appear to defluorinate isoflurane, but those induced by β-naphthoflavone do not. From a comparison of the extent of defluorination of isoflurane in hepatic microsomes from phenobarbital- and pregnenolone-16α-carbonitrile-pretreated rats, and their Kₘ and Vₘₐₓ values, it appears that isoflurane is defluorinated by one or more isozymes induced by both phenobarbital and pregnenolone-16α-carbonitrile. The major isozyme is probably cytochrome P-450PCN1. The metabolites of isoflurane were identified in human and phenobarbital-induced rat hepatic microsomes. In microsomes from phenobarbital-pretreated rats, isoflurane is metabolised to fluoride ion and trifluoroacetaldehyde; trifluoroacetic acid is not produced in measureable amounts. The trifluoroacetaldehyde produced binds to microsomal constituents. In human hepatic microsomes, the organofluorine metabolite is identified as trifluoroacetic acid. It is proposed that isoflurane is metabolised by different pathways in human and phenobarbital-induced rat hepatic microsomes. The interaction of isoflurane with the cyanide-sensitive factors was assessed by several criteria. Firstly, using the reoxidation of cytochrome b₅ as an index of fatty acid desaturase activity, isoflurane appears to interact with the Δ6- and/or Δ5-desaturases, but not the Δ9-desaturase. Secondly, these results were confirmed and clarified by the use of direct assays to measure the fatty acid desaturase activity. Using the direct assay, we confirmed that isoflurane did not inhibit the Δ9-desaturase and inhibited Δ6-desaturation of linoleic acid, but not the Δ6-desaturation of α-linolenic acid. The inhibition of the Δ6-desaturation of linoleic acid occurred at low millimolar concentrations of isoflurane. lsoflurane inhibits the Δ5-desaturation of eicosa-8, 11, 14-trienoic acid to a small extent which is only apparent at much higher concentrations of isoflurane than that which inhibits the Δ6-desaturase. Further studies focussed on measurement of the activity of Δ6-desaturase in order to attempt to study the kinetics of the inhibition of the Δ6-desaturase by isoflurane: Δ6-desaturase activity was assessed using hepatic microsomes as the source of the enzyme and linoleic acid as substrate precursor. In the course of these studies, we identified a number of factors that affected the apparent activity of the Δ6-desaturase in hepatic microsomes. These included significant levels of endogenous substrate and competing reactions in the hepatic microsomes. Endogenous substrate levels were quantified and corrected for. We then resorted to computer modelling to extract the kinetics of the Δ6-desaturase free of contributions from acyl-CoA synthetase and lysophospholipid acyltransferase, as well as enzyme decay. The kinetics of isoflurane inhibition of the Δ6-desaturase were then superimposed and studied by computer modelling.

by Lawrence Chi-ming Chiu. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1994. / Includes bibliographical references (leaves 142-151). / Abstract --- p.i / Acknowledgments --- p.iv / Table of Contents --- p.v / List of Figures --- p.vii / List of Tables --- p.xi / List of Abbreviations --- p.xii / Chapter Chapter 1: --- Introduction / Chapter 1.1 --- Polysaccharide-peptide (PSP ) --- p.1 / Chapter 1.2 --- Paracetamol (APAP ) --- p.6 / Chapter 1.2.1 --- Metabolism of APAP --- p.9 / Chapter 1.2.2 --- Mechanisms of APAP toxicity --- p.11 / Chapter 1.2.3 --- Factors influencing the hepatotoxicity of APAP --- p.17 / Chapter 1.3 --- Aim of the present study --- p.23 / Chapter Chapter 2: --- Studies on the effects of PSP on APAP-hepatotoxicity and glutathione levels / Chapter 2.1 --- Introduction --- p.25 / Chapter 2.2 --- Materials and methods --- p.30 / Chapter 2.3 --- Results / Chapter 2.3.1 --- The effects of PSP on APAP-induced hepatotoxicity --- p.41 / Chapter 2.3.2 --- The acute and sub-chronic effects of PSP on glutathione in rats --- p.45 / Chapter 2.4 --- Discussions --- p.66 / Chapter Chapter 3: --- Studies on the effects of PSP on the covalent binding and metabolism of APAP / Chapter 3.1 --- Introduction --- p.79 / Chapter 3.2 --- Materials and methods --- p.85 / Chapter 3.3 --- Results / Chapter 3.3.1 --- The effects of PSP on the covalent binding of radiolabelled paracetamol (14C-APAP ) in vitro --- p.102 / Chapter 3.3.2 --- The effects of PSP on the metabolism of APAP --- p.107 / Chapter 3.4 --- Discussions --- p.119 / Chapter Chapter 4: --- Conclusion --- p.137 / References --- p.142

Wang Deqing. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (p. 236-277). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.