Prevention of iron- and copper-mediated DNA damage by catecholamine and amino acid neurotransmitters, L-DOPA, and curcumin: metal binding as a general antioxidant mechanism.

Concentrations of labile iron and copper are elevated in patients with neurological disorders, causing interest in metal-neurotransmitter interactions. Catecholamine (dopamine, epinephrine, and norepinephrine) and amino acid (glycine, glutamate, and 4-aminobutyrate) neurotransmitters are antioxidants also known to bind metal ions. To investigate the role of metal binding as an antioxidant mechanism for these neurotransmitters, L-dihydroxyphenylalanine (L-DOPA), and curcumin, their abilities to prevent iron- and copper-mediated DNA damage were quantified, cyclic voltammetry was used to determine the relationship between their redox potentials and DNA damage prevention, and UV-vis studies were conducted to determine iron and copper binding as well as iron oxidation rates. In contrast to amino acid neurotransmitters, catecholamine neurotransmitters, L-DOPA, and curcumin prevent significant iron-mediated DNA damage (IC(50) values of 3.2 to 18 µM) and are electrochemically active. However, glycine and glutamate are more effective at preventing copper-mediated DNA damage (IC(50) values of 35 and 12.9 µM, respectively) than L-DOPA, the only catecholamine to prevent this damage (IC(50) = 73 µM). This metal-mediated DNA damage prevention is directly related to the metal-binding behaviour of these compounds. When bound to iron or copper, the catecholamines, amino acids, and curcumin significantly shift iron oxidation potentials and stabilize Fe(3+) over Fe(2+) and Cu(2+) over Cu(+), a factor that may prevent metal redox cycling in vivo. These results highlight the disparate antioxidant activities of neurotransmitters, drugs, and supplements and highlight the importance of considering metal binding when identifying antioxidants to treat and prevent neurodegenerative disorders.

Preventing metal-mediated oxidative DNA damage with selenium compounds.

Copper and iron are two widely studied transition metals associated with hydroxyl radical (˙OH) generation, oxidative damage, and disease development. Because antioxidants ameliorate metal-mediated DNA damage, DNA gel electrophoresis assays were used to quantify the ability of ten selenium-containing compounds to inhibit metal-mediated DNA damage by hydroxyl radical. In the Cu(I)/H(2)O(2) system, selenocystine, selenomethionine, and methyl-selenocysteine inhibit DNA damage with IC(50) values ranging from 3.34 to 25.1 µM. Four selenium compounds also prevent DNA damage from Fe(II) and H(2)O(2). Additional gel electrophoresis experiments indicate that Cu(I) or Fe(II) coordination is responsible for the selenium antioxidant activity. Mass spectrometry studies show that a 1 : 1 stoichiometry is the most common for iron and copper complexes of the tested compounds, even if no antioxidant activity is observed, suggesting that metal coordination is necessary but not sufficient for selenium antioxidant activity. A majority of the selenium compounds are electroactive, regardless of antioxidant activity, and the glutathione peroxidase activities of the selenium compounds show no correlation to DNA damage inhibition. Thus, metal binding is a primary mechanism of selenium antioxidant activity, and both the chemical functionality of the selenium compound and the metal ion generating damaging hydroxyl radical significantly affect selenium antioxidant behavior.

Antioxidant activity of sulfur and selenium: a review of reactive oxygen species scavenging, glutathione peroxidase, and metal-binding antioxidant mechanisms.

It is well known that oxidation caused by reactive oxygen species (ROS) is a major cause of cellular damage and death and has been implicated in cancer, neurodegenerative, and cardiovascular diseases. Small-molecule antioxidants containing sulfur and selenium can ameliorate oxidative damage, and cells employ multiple antioxidant mechanisms to prevent this cellular damage. However, current research has focused mainly on clinical, epidemiological, and in vivo studies with little emphasis on the antioxidant mechanisms responsible for observed sulfur and selenium antioxidant activities. In addition, the antioxidant properties of sulfur compounds are commonly compared to selenium antioxidant properties; however, sulfur and selenium antioxidant activities can be quite distinct, with each utilizing different antioxidant mechanisms to prevent oxidative cellular damage. In the present review, we discuss the antioxidant activities of sulfur and selenium compounds, focusing on several antioxidant mechanisms, including ROS scavenging, glutathione peroxidase, and metal-binding antioxidant mechanisms. Findings of several recent clinical, epidemiological, and in vivo studies highlight the need for future studies that specifically focus on the chemical mechanisms of sulfur and selenium antioxidant behavior.

Metal specificity in DNA damage prevention by sulfur antioxidants.

Metals such as CuI and FeII generate hydroxyl radical (.OH) by reducing endogenous hydrogen peroxide (H2O2). Because antioxidants can ameliorate metal-mediated oxidative damage, we have quantified the ability of glutathione, a primary intracellular antioxidant, and other biological sulfur-containing compounds to inhibit metal-mediated DNA damage caused hydroxyl radical. In the CuI/H2O2 system, six sulfur compounds, including both reduced and oxidized glutathione, inhibited DNA damage with IC50 values ranging from 3.4 to 12.4 microM. Glutathione and 3-carboxypropyl disulfide also demonstrated significant antioxidant activity with FeII and H2O2. Additional gel electrophoresis and UV-vis spectroscopy studies confirm that antioxidant activity for sulfur compounds in the CuI system is attributed to metal coordination, a previously unexplored mechanism. The antioxidant mechanism for sulfur compounds in the FeII system, however, is unlike that of CuI. Our results demonstrate that glutathione and other sulfur compounds are potent antioxidants capable of preventing metal-mediated oxidative DNA damage at well below their biological concentrations. This novel metal-binding antioxidant mechanism may play a significant role in the antioxidant behavior of these sulfur compounds and help refine understanding of glutathione function in vivo.

The central role of metal coordination in selenium antioxidant activity.

Oxidative DNA damage occurs in vivo by hydroxyl radical generated in metal-mediated Fenton-type reactions. Cell death and mutation caused by this DNA damage are implicated in neurodegenerative and cardiovascular diseases, cancer, and aging. Treating these conditions with antioxidants, including highly potent selenium antioxidants, is of growing interest. Gel electrophoresis was used to directly quantify DNA damage inhibition by selenium compounds with copper and H(2)O(2). Selenocystine inhibited all DNA damage at low micromolar concentrations, whereas selenomethionine showed similar inhibition at 40 times these concentrations, and 2-aminophenyl diselenide showed no effect. DNA damage inhibition by these selenium compounds does not correspond to their glutathione peroxidase activities, and UV-vis and gel electrophoresis results indicate that selenium-copper coordination is essential for DNA damage inhibition. Understanding this novel metal-coordination mechanism for selenium antioxidant activity will aid in the design of more potent antioxidants to treat and prevent diseases caused by oxidative stress.