Chemico-biological interactions of sulfide and organosulfur compounds.
Published: 2004
Language: eng
Number of pages: 201
Description: Exposure of isolated hepatocytes to NaHS led to GSH depletion. CYP450 inhibitors were protective against NaHS toxicity and prevented GSH depletion. Methionine was protective against NaHS and its effect was overcome by inhibition of S-adenosyl-L-homocysteine hydrolase by adenosine. This suggests that S-adenosyhnethionine dependent methylation can detoxify H2S in the liver. The H 2O2 scavengers were protective against H2S toxicity. H2S induced ROS formation was dose dependent and pyruvate inhibited this ROS production. Nontoxic concentrations of H2S enhanced the cytotoxicity of H2O2 generated by glucose/glucose oxidase, which was inhibited by CYP450 inhibitors. Furthermore hepatocyte ROS formation induced by H2S was decreased by CYP450 inhibitors cimetidine and benzyleimidazole. Therefore CYP450-dependent metabolism of H2S is responsible for inducing ROS production. H2S induced cytotoxicity was preceded by mitochondrial depolarization.In this project, two aspects of the action of hydrogen sulfide and reactive sulfur species have been studied: cytotoxic and cytoprotective effects. Freshly isolated hepatocytes have been used in order to examine the prevalence and mechanisms of the different sulfide dependent processes that influence cell survival and death. Our hypothesis is that the exogenous application of high concentrations of HS and other reactive sulfur species to isolated hepatocytes in the presence of various modulators will provide a rapid mechanism dependent screen for ways in which reactive sulfur species can modulate cell survival and death.NaHS and/or garlic/onion derived organosulfur compounds, Allyl mercaptan (AM) and Propyl mercaptan (PM) protected hepatocytes against hydroquinone, methylbenzoquinone, and 5-hydroxynaphtoquinone. NaHS and mercaptans increased the cytotoxicity of tert-butylhydroquinone. Treatment of these benzoquinones with allyl mercaptan, propanethiol or NaHS led to formation of new compounds which by MS/MS analysis were identified as mercaptan conjugates of corresponding hydroquinones. (Abstract shortened by UMI.)H2S, allyl mercaptan (AM), propyl mercaptan (PM), diallyl disulfide (DADS) and diallyl sulfide (DAS) prevented hepatocyte toxicity induced by allyl alcohol, 1-bromoethanol and their toxic metabolites. MS/MS spectrometry revealed adduct formation between AM and/or PM with the acrolein and/or haloacetaldehyde formed by the metabolism of allyl alcohol and alpha-haloethanol. H 2S or garlic and onion mercaptans are cytoprotective by trapping toxic aldehyde metabolites and/or by preventing lipid peroxidation.
Notes: Adviser: Peter Pennefather.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-05, Section: B, page: 2384.