Date of Award

8-2008

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Chemistry

Advisor

Brumaghim, Julia L

Committee Member

Arya , Dev P

Committee Member

Christensen , Kenneth

Committee Member

Hwu , Shiou-Jyh

Abstract

Polyphenol compounds are widely recognized for their antioxidant activity; however, under some conditions these compounds can also exhibit prooxidant activity. This work examined the interactions of polyphenols with iron and copper to improve understanding of both their antioxidant and prooxidant effects. Polyphenols with catechol and gallol groups effectively inhibit iron-mediated oxidative DNA damage by chelating iron, with IC50 values ranging from 1-59 µM. Gallate compounds are more potent than their catecholate analogues in every instance, and their antioxidant potencies correlate to pKa values for the most acidic phenolic hydrogen. This correlation represents the first predictive model of polyphenol antioxidant activity related to iron binding.
When polyphenol compounds bind Fe2+, O2 oxidizes the iron to Fe3+. Polyphenol-iron oxidation rates correlate to the measured IC50 values, indicating that both iron binding and iron oxidation play important roles in polyphenol antioxidant activity. In contrast, polyphenols inhibited Cu+-mediated DNA damage much less effectively than iron-mediated damage, and some polyphenols were prooxidants under these conditions. Because semiquinone radicals and hydroxyl radical adducts are detected by EPR spectroscopy in solutions of polyphenols, Cu+, and H2O2, it is likely that weak polyphenol-Cu+ interactions allow a redox-cycling mechanism, whereby all of the necessary reactants to cause DNA damage (Cu+, H2O2, and reducing agents) are regenerated. For those compounds that inhibit copper-mediated DNA damage, however, EPR evidence suggests that they follow a radical scavenging pathway. Inhibition of copper-mediated DNA damage has not previously been reported for these polyphenol compounds. This work has resulted in better models for predicting polyphenol antioxidant activity, and has highlighted the importance of the metal ion in determining polyphenol antioxidant and prooxidant behavior.

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