Preventing metal-mediated oxidative DNA damage with selenium compounds

Abstract

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.

Selenium‐containing amino acids as direct and indirect antioxidants

“…Replacement of Cu 1 with a 2,2 0 -bipyridine-Cu 1 complex abolished the protection (34), suggesting that this was mediated, at least in part, by metal ion coordination, though whether this directly involves the selenium atom is less clear. Evidence for Fe 21 -Se complexes with both selenocystine and SeMet has also been provided in a Fe 21 /H 2 O 2 system (35), but in this case, no DNA protection was observed (35). It should be noted that in the Cu experiments the presence of the 2,2 0 -bipyridine ligand will affect the redox chemistry of the Cu 1 and this may explain, at least in part, these observations.…”

“…Incubation of selenocystine (Sec-Sec) or SeMet with a HO À producing Cu 1 /H 2 O 2 system was reported to yield Cu 1 :Se complexes (with 1:1 and 1:2 stoichiometries for both compounds, and also 1:3 for SeMet) with this protecting supercoiled plasmid DNA from oxidation (34,35). Replacement of Cu 1 with a 2,2 0 -bipyridine-Cu 1 complex abolished the protection (34), suggesting that this was mediated, at least in part, by metal ion coordination, though whether this directly involves the selenium atom is less clear.…”

DNA-bound metal ions: recent developments

“…The organoselenium compounds selenocysteine and selenomethionine function as antioxidants in reactions involving Cu(I) through coordinating the Cu ions (55,56). Methyl-selenocysteine exhibited the ability to minimize oxidative DNA damage by coordinating both Cu(I) and Fe(II), and whereas selenocystamine exhibited antioxidant activity for reactions involving both Cu(I) and Fe(II), there was evidence that it formed a coordination complex only with Fe(II) (56).…”

“…Methyl-selenocysteine exhibited the ability to minimize oxidative DNA damage by coordinating both Cu(I) and Fe(II), and whereas selenocystamine exhibited antioxidant activity for reactions involving both Cu(I) and Fe(II), there was evidence that it formed a coordination complex only with Fe(II) (56). The inorganic Se compounds Se dioxide (SeO 2 ) and sodium selenite [Na 2 SeO 3 , which dissociates in aqueous solution to produce the selenite ion (SeO 3 2-)], also appear to function as antioxidants in reactions involving Fe(II), Cu(II), and Cr(III) by coordinating these metal ions (57,58).…”

Selenium in the therapy of neurological diseases. Where is it going?

“…The same result was observed in rats that were kept on a Se-deficient diet up to 6 generations. Although a drastic decrease in the level of Se in skeletal muscles, liver and blood was observed, only a small Se decline in the brain was reported in these animals [12,26]. It was also shown that after injection of a radiochemical labelled SeO 3 2-in rats on basal feed devoid of Se, the highest uptake of the radiotracer ( 75 Se) was observed in the brain, in contrast to selenium-adequate nourished rats, where a quite ubiquitous distribution of 75 Se was observed [27].…”