Date of Award

1-3-2003

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

David O Lamsbeth

Second Advisor

William Johnson

Abstract

The location and function of the electron transport chain render the mitochondria the primary source for potentially damaging reactive oxygen species in aerobic cells. Normally, the concentration of superoxide anion in mitochondria is controlled, at least in part, by the sequential action of superoxide dismutase (SOD) and catalase. However, when the terminal steps of the electron transport are impaired or inhibited, superoxide anion production may rise to levels that overwhelm the normal protective enzymes. Studies have shown that copper deficiency causes a reduction in the activity of cytochrome-c oxidase, the copper dependent, terminal respiratory complex of the electron transport chain. Copper deficiency has also been shown to increase the transcriptional rate for MnSOD in vivo. Hypothetically, under conditions of decreased copper, cytochrome-c oxidase function is impaired resulting in an increase in ROS production and the subsequent increase in MnSOD levels. In order to test this hypothesis, copper-adequate and copper-deficient HL-60 cells were analyzed. Furthermore, to elucidate if the treatment of copper-deficient cells with antioxidants would decrease the associated oxidative stress, copper-adequate and copper-deficient HL-60 cells were treated with vitamin C, vitamin E or resveratrol. The treatment of copper-deficient cells with vitamins C and E was accompanied by marked growth inhibition and decreased viability, whereas the copper-adequate cells displayed no adverse effects. Resveratrol was not well tolerated in either group. Although certain antioxidants may induce apoptosis in some cell lines and increase proliferation in others, these opposing effects have not been found in the same cell system. To determine if the growth inhibitory and antiproliferative effects of the antioxidant treatments are associated with programmed cell death rather than necrosis, several characteristic apoptotic events were examined. Results of this research suggest that copper deficiency reduces cytochrome-c oxidase function which in turn causes an increase in ROS production. The ROS affect the cell system through cell signaling mechanisms and/or through oxidative damage. Presumably, the redox status of the cell is altered, rendering these cells more sensitive to apoptotic stimuli.

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