Item – Theses Canada

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OCLC number
1032937243
Link(s) to full text
LAC copy
LAC copy
Author
MacAllister, Stephanie.
Title
Investigating the Cytotoxic Mechanisms of Hepatotoxicity Induced by Xenobiotics and their Metabolites.
Degree
(PhD)--University of Toronto, 2013.
Publisher
Toronto : University of Toronto, 2013.
Description
1 online resource
Notes
Includes bibliographical references.
Abstract
Xenobiotics or their metabolite(s) can be electrophilic or free radicals that elicit a variety of chemical reactions either directly or indirectly effecting the biochemistry of a cell, resulting in oxidative stress and/or cell death. Because drug-induced liver injury (DILI) is the leading cause of death from acute liver failure and the most common cause of drug withdrawals from the market, understanding and identifying hepatotoxic mechanisms have become a major focus area with drug and environmental regulatory agencies. In the following chapters, the in vitro cytotoxic mechanisms of known hepatotoxins were investigated using the 'Accelerated Cytotoxicity Mechanism Screening' (ACMS) technique. The following hypothesis was formulated: the ACMS technique can be utilized as a basic toxicological screening model to assess xenobiotic-induced hepatocyte toxicity. Using this technique, the following investigation provides support for the validity of an inflammatory model using glucose and glucose oxidase to generate hydrogen peroxide (H2O2) and its effects on known hepatotoxins, including nitroaromatic drugs (nimesulide, nilutamide, flutamide), aromatic amine drugs (clozapine, thioridazine), ethanol and its metabolite acetaldehyde. Using this inflammatory model, cytotoxicity increased with all examined compounds. This thesis also examined the hepatotoxicity of chlorpromazine (CPZ) and its reactive metabolites. Toxic CPZ metabolites were generated by cytochrome P450 (CYP) or peroxidase/H2O2-catalysed oxidation of CPZ resulting in loss of hepatocyte viability, collapse in mitochondrial membrane potential (MMP) and increased glutathione (GSH) oxidation. Finally, this thesis investigated the molecular targets of acrolein and chloroacetaldehyde (CAA), reactive metabolites of anticancer agents cyclophosphamide/ifosfamide, and the subsequent protective capacities of various protecting agents in both cell- and cell-free models. This study could provide a better understanding into the therapeutic value of protective agents currently being prescribed and agents not currently being used, but which have demonstrated protecting effects against acrolein, CAA or other toxic aldehydes. There are needs for basic toxicology screening models to assess and categorize the hepatotoxic risks associated with xenobiotics, including drugs and environmental toxins. The ACMS technique may be such a model and have a valuable application that may be 1) adaptable for high-throughput screening, 2) useful for supplementing existing in vitro screening techniques as a means to accelerate the pre-clinical screening process and 3) result in a better understanding of environmental pollutants.
Other link(s)
tspace.library.utoronto.ca
hdl.handle.net
Subject
Toxicology.