In vitro assessment of acute and chronic toxicity of lovastatin to cultured HepG2 hepatoma cells

El-Karawy, Nagwa M. (1996) In vitro assessment of acute and chronic toxicity of lovastatin to cultured HepG2 hepatoma cells. Masters thesis, Memorial University of Newfoundland.

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    Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission.
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Abstract

The investigations reported here highlight the cytotoxic effect of 3-Hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) Reductase inhibition by lovastatin on the cultured human hepatoma cell line HepG2. This investigation focused on the toxic effects of lovastatin at exposure levels at and above those currently used clinically. The laboratory approaches used included electron microscopy, cell cycle analysis by flow cytometry, investigation of peripheral cell damage by enzyme leakage and other protein studies, and analysis of intracellular and extracellular lipids for various exposure concentrations and times. The experiments were also extended to consider the effects of adding oleic acid to the cell cultures as a nutritional supplement to enhance lipogenesis. The findings are discussed in light of current understanding on the significance of protein prenylation on the cell cycle and the mechanisms of cell death by necrosis and apoptosis. The lower lovastatin concentrations used in this study (0.1 - 2.5 μM) did not kill cells, even after exposure for 8 days. However, if cell cultures containing otherwise nontoxic lovastatin concentrations were supplemented with oleic acid/BSA, cell viability was significantly reduced at all lovastatin concentrations (α=0.05). This work shows that lovastatin supplemented by fatty acid can significantly affect HepG2 cell morphology and functions. The results of this work suggest also that HepG2 cells could be used as an efficient and practical model system to investigate the process of cell death in vivo. Also, it is a convenient model for investigations on mevalonate-dependent cellular mechanisms. This study provides evidence to support the potential role of lovastatin treatment in cancer management.

Item Type: Thesis (Masters)
URI: http://research.library.mun.ca/id/eprint/4054
Item ID: 4054
Additional Information: Bibliography: leaves 115-130.
Department(s): Science, Faculty of > Biochemistry
Date: 1996
Date Type: Submission
Library of Congress Subject Heading: Hydroxymethylglutaryl coenzyme A reductases--Inhibitors; Enzyme inhibitors--Toxicology; Lovastatin--Toxicology; Oleic acid--Toxicology; Hepatoma

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