Other antioxidant mechanisms

It was shown by Balasubramanian et al. [51] that mixtures of non-esterified fatty acids, isolated from intestinal brush-order cells, were powerful inhibitors of lipid peroxidation apparently quite substantial amounts of free fatty acids are present in these cells. Subsequent work showed that the principal active constituent of this lipid mixture was oleic acid [52], and that it is highly likely that the mode of action of inhibition by the monounsaturated fatty acids of lipid peroxidation involves complexing transition metals which are therefore not available to act as catalysts in the peroxidation mechanism [53]. 

Formation of free radicals and mechanisms of action in normal biochemical processes and pathological states 

Reader in Biochemistry, Free Radical Research Group, United Medical and Dental Schools, Guy s St. Thomas s Hospital, 

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The main function of metal deactivators (MD) is to retard efficiently metal-catalyzed oxidation of polymers. Polymer contact with metals occur widely, for example, when certain fillers, reinforcements, and pigments are added to polymers, and, more importantly when polymers, such as polyolefins and PVC, are used as insulation materials for copper wires and power cables (copper is a pro-oxidant since it accelerates the decomposition of hydroperoxides to free radicals, which initiate polymer oxidation). The deactivators are normally poly functional chelating compounds with ligands containing atoms like N, O, S, and P (e.g., see Table 1, AOs 33 and 34) that can chelate with metals and decrease their catalytic activity. Depending on their chemical structures, many metal deactivators also function by other antioxidant mechanisms, e.g., AO 33 contains the hindered phenol moiety and would also function as CB-D antioxidants. 

Several studies indicate that catechins and procyanidins are powerful scavengers of ROS. Some findings regarding the antioxidant activity of proanthocyanidins are listed in Ref. [100]. Other antioxidant mechanisms are the chelation of transition metals, as well as the mediation and inhibition of enzymes. The metal-chelating activity of proanthocyanidins is thought to be due to their capacity to reduce the concentration, and thus the oxidative activity, of hydroxyl radicals formed by Fenton reaction catalyzed by iron or copper. Flavanols also influence oxidative stress via enzyme modification and modulation of cell signaling pathways the extent of the effect relies greatly on flavanol structure-related protein reactivity [101]. 

A variety of other metals and their complexes have been studied for radioprotective activity. Among these are copper glycinate, strontium chloride, ZnNa -diethylenetriaminepentaacetate (ZnDTPA), and selenium, which has been studied because of its relationship to endogenous antioxidant mechanisms, especiaHy GSH peroxidase and vitamin E. 

Similar to some other antioxidants, pyrrolopyrimidines do not contain active free radical scavenging groups such as phenolic or thiolic substituents. At present, at least two different mechanisms of their antioxidant activity have been proposed [307], It was suggested that pyrrolopyrimidines, which are electron donating compounds, can be oxidized by hydroxyl or peroxyl radicals or hydroxylated by cytochrome P-450 forming phenolic metabolite... 

On the other hand, several ROS are highly cytotoxic. Consequently, eukaryotic cells have developed an elaborate arsenal of antioxidant mechanisms to neutrahze their deleterious effects (enzymes such as superoxide dismutases, catalases, glutathione peroxidases, thioredoxin inhibitors of free-radical chain reaction such as tocopherol, carotenoids, ascorbic acid chelating proteins such as lactoferrin and transferrin). It can be postulated that ROS may induce an oxidative stress leading to cell death when the level of intracellular ROS exceeds an undefined threshold. Indeed, numerous observations have shown that ROS are mediators of cell death, particularly apoptosis (Maziere et al., 2000 Girotti, 1998 Kinscherf et al., 1998 Suzuki et al., 1997 Buttke and Sanstrom, 1994 Albina et al., 1993). 

Other chemical mechanisms must be involved with the other antioxidants in this study because of their differing chemical constitution. The degree to which these various agents induce or activate preexisting oxidative protection mechanisms in cells remains speculative at present. 

For some time, the effects of and responses to vitamin E have been interpreted in terms of an antioxidant mechanism of action. However, several observations have raised the question as to whether other mechanisms could be involved. For example, the effects of selenium and vitamin E on growth and polyunsaturated fatty acid synthesis in cultured mouse fibroblasts could not be reproduced by artificial antioxidants [198, 199]. The specific requirement of (+ )-a-toco-pherol for the phenotypic differentiation of the rotifer [200] may not be through an antioxidant mechanism. The effects of vitamin E on differentiation of neuroblastoma cells [201] and metamorphosis of various species [202] are likely to be due to a growth-factor-like action. A study on the interaction... 

The mechanism of melatonin s interaction with reactive species probably involves donation of an electron to form the melatoninyl cation radical or through a radical addition at the site C3. Other possibilities include hydrogen donation from the nitrogen atom or substitution at position C2, C4, and C7 and nitrosation [169]. The mechanisms by which melatonin protects against LP most likely involve direct or indirect antioxidant and free-radical scavenging activities of this indoleamine [169,171]. 2-Phenyl indole derivatives have redox properties because of the presence of an electron-rich aromatic ring system that allows the indoleamine to easily function as an electron donor. For these derivatives, the possible antioxidant mechanism might be most probably toward carbon-centered radicals described by Antosiewicz et al. [172]. 

The correlation between dietary carotenoids and the carotenoids rontinely found in the extracts from human serum/plasma has revealed that only selected groups of carotenoids make their way into the human bloodstream. Some of these carotenoids are absorbed intact and others such as lutein, zeaxanthin, and lycopene are presumably converted to several metabolites. - In addition to their antioxidant mechanism... 

The following questions remain open. In some cases differential effects of a-tocopherol and P-tocopherol have been found, pointing to a non-antioxidant mechanism at the basis of gene regulation [31,36]. In other cases, however, only a-tocopherol has been tested leaving the mechanism of a-tocopherol action unclarified. Furthermore, the... 

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