Date of Graduation

2002

Document Type

Dissertation/Thesis

Abstract

Metals have been indicated in causing generation of reactive oxygen species (ROS) and cellular injury. The overall objective of the present study was to investigate ROS generation from metals and the related effects on biological systems. The results obtained from the present studies have demonstrated that: (a) Cobalt is capable of generating ·OH via a Co(I)-mediated Fenton-like reaction. (b) The ·OH radical is generated by reaction of H2O2 with Cr(V), which is produced by enzymatic one-electron reduction of Cr(VI). H2O2 is produced by reduction of molecular oxygen via O2·− as an intermediate. The ·OH radicals generated by these reactions are capable of causing DNA strand breaks, which can be inhibited by catalase, formate and experiments performed under argon. (c) Most studies concerning the Cr(VI)-mediated free radical generation and related cellular injury have been limited to soluble Cr(VI). Various studies have shown that solubility is an important factor contributing to the carcinogenic potential of Cr(VI) compounds. The results obtained show that reduction of insoluble PbCrO4 by glutathione reductase/NADPH generates ·OH radicals. The mechanism of ·OH generation involves reduction of molecular oxygen to H2O2, which generates ·OH radicals through a Fenton-like reaction. The ·OH radicals generated by PbCrO4 caused DNA strand breakage. (d) Wood smoke is also able to cause lipid peroxidation, activate nuclear transcription factor, NF-κB, and enhance the release of TNF-α from RAW 264.7 cells. The results indicate that the free radicals generated by wood smoke through the reaction of Fe with H2O 2 are able to cause DNA and cellular damage and may act as a fibrogenic agent. (e) Results of investigations indicate that ascorbic acid is only one facet of the free radical protection effect of fruit and vegetable juices. The consumption of whole fruits and vegetables appears to be superior to an ascorbic acid supplement for antioxidant effectiveness. (f) ESR spectroscopic and imaging measurements were performed using the nitroxide spin labels 4-hydroxy-2,2,6,6-tetramethylpiperidine-1- 15N-1-oxyl (TEMPOL) and 3-carbanoylproxyl (3-CP). These findings help our understanding of metal-induced free radical generation and its related cellular injury.

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