Date of Award

1996

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Daniel F. Church

Abstract

Lipid peroxidation is the process by which lipids in the cell membrane undergo free radical-initiated oxidation. The resulting cell damage has been implicated in the onset of many diseases, including as cancer, aging, and stroke. Lipid oxidation has been studied in a variety of membrane models, including homogeneous solution, micelles, liposomes, and microsomes. The kinetics for free radical reactions proven to occur during lipid oxidation in homogeneous solution have been thoroughly elucidated. These kinetics were also shown to apply to oxidation in micelles. This dissertation presents evidence that the kinetics of more biologically realistic membrane models such as liposomes may be quite different. Antioxidants such as $\alpha$-tocopherol ($\alpha$-T) have been shown to inhibit lipid oxidation. Work presented here suggests that the efficiency with which antioxidants inhibit oxidation is dependent on the structure of the membrane model. It was observed that the antioxidant efficiency of $\alpha$-T decreases dramatically from homogeneous to heterogeneous systems of lipid, including micelles, liposomes, and microsomes. This could be due to a decrease in fluidity in the membrane model, limiting the diffusion of $\alpha$-T. A less mobile antioxidant may have fewer opportunities for encountering and trapping free radicals. Addition of free fatty acids (FFA) to the membrane model to mimic damaged tissue enhanced $\alpha$-T's efficiency. Differential Scanning Calorimetry data show there is an increase in fluidity when FFA are present, indicating $\alpha$-T should then diffuse more readily through the membrane. This work thus demonstrates that while $\alpha$-T appears effective in homogeneous solution, micelles, and liposome models of damaged membranes, its antioxidant efficiency is much smaller in biologically relevant models for normal tissues. Furthermore, the concentration of $\alpha$-T required to inhibit oxidation in liposomes is greater than that which exists in tissues in vivo. Finally, the antioxidant effectiveness of several synthetic antioxidant drugs called 21-aminosteroids was compared with that of $\alpha$-T. It is shown here that $\alpha$-T is much more effective than any of the 21-aminosteroids. In addition, the 21-aminosteroids were shown to be much less effective below pH 7.0. This may be important in damaged tissue, where the pH reportedly falls to as low as 5.9.

ISBN

9780591133493

Pages

118

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