No abstract is provided for this article.
There is considerable dispute about whether the hydroxylating ability of peroxynitrite (ONOO-)-derived species involves hydroxyl radicals (OH*). This was investigated by using salicylate and phenylalanine, attack of OH* upon which leads to the formation of 2, 3– and 2, 5-dihydroxybenzoates, and o-, m- and p-tyrosines respectively. On addition of ONOO- to salicylate, characteristic products of hydroxylation (and nitration) were observed in decreasing amounts with rise in pH, although added products of hydroxylation of salicylate were not recovered quantitatively at pH 8.5, suggesting further oxidation of these products and underestimation of hydroxylation at alkaline pH. Hydroxylation products decreased in the presence of several OH* scavengers, especially formate, to extents similar to those obtained when hydroxylation was achieved by a mixture of iron salts, H2O2 and ascorbate. However, OH* scavengers also inhibited formation of salicylate nitration products. Ortho, p- and m-tyrosines as well as nitration products were also observed when ONOO- was added to phenylalanine. The amounts of these products again decreased at high pH and were decreased by addition of OH* scavengers. We conclude that although comparison with Fenton systems suggests OH* formation, simple homolytic fission of peroxynitrous acid (ONOOH) to OH* and NO2 would not explain why OH* scavengers inhibit formation of nitration products.
The first life forms evolved in a highly reducing environment. This reduced state is still carried by cells today, which makes the concept of “reductive stress” somewhat redundant. When oxygen became abundant on the Earth, due to the evolution of photosynthesis, life forms had to adapt or become extinct. Living organisms did adapt, proliferated and an explosion of new life forms resulted, using reactive oxygen species (ROS) to drive their evolution. Adaptation to oxygen and its reduction intermediates necessitated the simultaneous evolution of select antioxidant defences, carefully regulated to allow ROS to perform their major roles. Clearly this “oxidative stress” did not cause a major problem to the evolution of complex life forms. Why not? Iron and oxygen share a close relationship in aerobic evolution. Iron is used in proteins to transport oxygen, promote electron transfers, and catalyse chemical reactions. In all of these functions, iron is carefully sequestered within proteins and restricted from reacting with ROS, this sequestration being one of our major antioxidant defences. Iron was abundant to life forms before the appearance of oxygen. However, oxygen caused its oxidative precipitation from solution and thereby decreased its bioavailability and thus the risk of iron-dependent oxidative damage. Micro-organisms had to adapt and develop strategies involving siderophores to acquire iron from the environment and eventually their host. This battle for iron between bacteria and animal hosts continues today, and is a much greater daily threat to our survival than “oxidative stress” and “redox stress”.
Foods and beverages rich in phenolic compounds, especially flavonoids, have often been associated with decreased risk of developing several diseases. However, it remains unclear whether this protective effect is attributable to the phenols or to other agents in the diet. Alleged health-promoting effects of flavonoids are usually attributed to their powerful antioxidant activities, but evidence for in vivo antioxidant effects of flavonoids is confusing and equivocal. This may be because maximal plasma concentrations, even after extensive flavonoid intake, may be low (insufficient to exert significant systemic antioxidant effects) and because flavonoid metabolites tend to have decreased antioxidant activity. Reports of substantial increases in plasma total antioxidant activity after flavonoid intake must be interpreted with caution; findings may be attributable to changes in urate concentrations. However, phenols might exert direct effects within the gastrointestinal tract, because of the high concentrations present. These effects could include binding of prooxidant iron, scavenging of reactive nitrogen, chlorine, and oxygen species, and perhaps inhibition of cyclooxygenases and lipoxygenases. Our measurements of flavonoids and other phenols in human fecal water are consistent with this concept. We argue that tocopherols and tocotrienols may also exert direct beneficial effects in the gastrointestinal tract and that their return to the gastrointestinal tract by the liver through the bile may be physiologically advantageous.
Sixteen plant-derived or synthetic coumarins with various hydroxyl and other substitutions were tested for their ability to inhibit lipid peroxidation and to scavenge hydroxyl radicals, superoxide radicals and hypochlorous acid. Seven unsubstituted or monosubstituted coumarins were essentially inactive in all tests except for ability to scavenge OH with rate constants ⪸1 × 109 M−1. sec−1. Of the remaining nine, six containing dihydroxy substitutions were effective inhibitors of Fe3+-ascorbate-dependent microsomal lipid peroxidation ( ic 50 < 20 μM), with ortho-dihydroxy + one additional substitution optimal ( ic 50 < 10 μM). ortho-Dihydroxylated coumarins were pro-oxidant (enhanced OH. generation) in the Fe3+-EDTA-H2O2 deoxyribose system but decreased OH generation in the Fe3+- ascorbate-H2O2 deoxyribose system, indicating that these compounds can both chelate iron ions and also readily donate electrons for redox cycling of Fe3+. The meta-dihydroxycoumarin did not show this behaviour, but was an effective scavenger of hypochlorous acid, a property shared by only one other compound. Several other coumarins with one or more hydroxyl substituents were also capable of effectively removing Superoxide anions (ic 50 3.7–72 μM), although some could not be quantified due to direct rapid reduction of cytochrome c. We conclude that several compounds, notably 5,7-dihydroxy-4-methylcoumarin, possess beneficial biochemical profiles of interest in relation to pathophysiological processes dependent upon reactive oxygen species.
During the chemical and biological evolution of the Earth, its atmosphere changed from a highly reducing state to the oxygen-rich state that we know today. Free molecular oxygen (dioxygen) probably appeared on the Earth's surface some 2 billion years ago as a result of photosynthetic microorganisms acquiring the ability to split water. Oxygen is now the most abundant element in the Earth's crust and the second most abundant element in the biosphere. The concentration of molecular oxygen (hereafter referred to as oxygen) in dry air has risen to 21%. Iron, the element of equal importance in this story, is the fourth most abundant element in the Earth's crust.
