Prevention of iron- and copper-mediated oxidative DNA damage by neurotransmitters and related compounds: Evidence for metal binding as an antioxidant mechanism.

摘要

An array of health concerns have been attributed to oxidative DNA damage from the hydroxyl radical (*OH), and the presence of the most biologically available metals iron and copper perpetuate the production of this radical through the Fenton and Fenton-like reactions, respectively. The concentrations at which flavonol and polyphenol antioxidants prevent 50% of DNA damage (IC50) were measured using gel electrophoresis assays upon Fe(II)/H2O 2- and Cu(I)/H2O2-mediated DNA damage (Chapter 2). Results show that catechol- and gallol-containing antioxidants differ greatly in preventing DNA damage by Cu(I)/H2O2, compared to Fe(II)/H2O2, behavior that was explained using electron paramagnetic resonance spectroscopy. Semiquinone and other radical formation indicated that some polyphenol compounds could promote copper redoxy cycling, leading to increased DNA damage and prooxidant activity. DNA damage assays also revealed that hydroxy-keto functional groups participate in preventing iron-mediated DNA damage prevention depending on the type of hydroxy-keto group present in the flavonolic compound (Chapter 2).;Concentrations of labile iron and copper are elevated in patients with neurological disorders, causing concern about metal-neurotransmitter interactions. Both catecholamine and amino acid neurotransmitters are known to bind these metals, and their antioxidant properties have been previously examined. To further investigate the extent to which metal-binding affects antioxidant activity, of both neurotransmitter types, their iron-mediated DNA damage inhibition was quantified, UV-vis studies were used to detect iron and copper binding, and cyclic voltammetry was used the determine redox potentials for these neurotransmitters with and without iron (Chapter 3). In contrast to the amino acid neurotransmitters, catecholamine neurotransmitters prevent iron-mediated DNA damage and are electrochemically active. When bound to iron, these catecholamines shift redox potentials outside the range for iron(II) generated *OH. Curcumin, a novel preventative treatment for Alzheimer's symptoms, also demonstrated the ability to prevent iron- and copper-mediated DNA damage (IC50 values of 28 and 55 &mgr;M, respectively) as well as versatile redox activity, indicating that metal binding can explain most of the antioxidant and prooxidant activity of these compounds, and this mechanistic insight will help in identifying antioxidants to treat and prevent neurodegenerative diseases.