Classic antioxidants

Classic antioxidants, vitamin E, vitamin C, and others can suppress the activation of apoptosis. For example, ascorbic acid prevented cytochrome c release and caspase activation in human leukemia cells exposed to hydrogen peroxide [128], Pretreatment with A -acctylcystcinc, ascorbate, and vitamin E decreased homocysteine thiolactone-induced apoptosis in human promyelocytic leukemia HL-60 cells [129]. Resveratrol protected rat brain mitochondria from anoxia-reoxygenation damage by the inhibition of cytochrome c release and the reduction of superoxide production [130]. However, it should be mentioned that the proapoptotic effect of ascorbate, gallic acid, or epigallocatechin gallate has been shown in the same human promyelocytic leukemia cells [131]. 

Vitamin A (retinol) is not a classic antioxidant although it is frequently related to a group of antioxidant vitamins E, C, and A. Murata and Kawanishi [83] found that retinol and its derivative retinal induced the formation of 8-HOdG in HL-60 cells. This process was supposedly mediated by hydroxyl radicals formed from hydrogen peroxide (the product of superoxide dismutation) and endogenous transition metal ions. 

As mentioned above, in contrast to classic antioxidant vitamins E and C, flavonoids are able to inhibit free radical formation as free radical scavengers and the chelators of transition metals. As far as chelators are concerned their inhibitory activity is a consequence of the formation of transition metal complexes incapable of catalyzing the formation of hydroxyl radicals by the Fenton reaction. In addition, as shown below, some of these complexes, for example, iron- and copper-rutin complexes, may acquire additional antioxidant activity. 

Figure 29.17). The first mechanism is untypical one for classical antioxidants and probably may be considered as a novel mode of antioxidant activity. The second one is typical for indirect antioxidants. 

Chelators of iron, which are now widely applied for the treatment of patients with thalassemia and other pathologies associated with iron overload, are the intravenous chelator desferal (desferrioxamine) and oral chelator deferiprone (LI) (Figure 19.23, see also Chapter 31). Desferrioxamine (DFO) belongs to a class of natural compounds called siderophores produced by microorganisms. The antioxidant activity of DFO has been studied and compared with that of synthetic hydroxypyrid-4-nones (LI) and classic antioxidants (vitamin E). It is known that chronic iron overload in humans is associated with hepatocellular damage. Therefore, Morel et al. [370] studied the antioxidant effects of DFO, another siderophore pyoverdin, and hydroxypyrid-4-ones on lipid peroxidation in primary hepatocyte culture. These authors found that the efficacy of chelators to inhibit iron-stimulated lipid peroxidation in hepatocytes decreased in the range of DFO > hydroxypyrid-4-ones > pyoverdin. It seems that other siderophores are also less effective inhibitors of lipid peroxidation than DFO [371],... 

The presence of the oxidized metabolites is unique and may provide additional reasons for the health benefits of lignans. Classical antioxidant mechanisms show that the addition of an ortho hydroxyl group to a monophenol enhances the antioxidant activity of the original monophenol. Thus, some of the mammalian lignan metabolites may actually have greater or different activity than the parent lignan. Kitts et al (1999) reported that enterolactone and enterodiol had greater antioxidant activity than the parent... 

The utility of classical antioxidants such as hindered amines, phenols, and nitrones for the stabilization of pristine polyacetylene (29), poly(methyl acetylene) (30), and poly(l,6-heptadiyne) (31) has been examined. Poly(methyl acetylene), although dopable to only low conductivities (10" S/cm), has similar oxidative behavior to polyacetylene and serves as a good model for other polyenes. In general, the improvement in stability of poly(methyl acetylene) was limited, but combinations of hindered phenols and hydroperoxide scavengers resulted in a factor of 5 decrease in the oxidation rate (30) as monitored by the appearance of IR absorption bands attributable to carbonyl groups. These degradation rates are still too high for the use of these polyenes in an unprotected environment. The compatibility of such stabilizers with the dopants commonly used for polyacetylene was not studied. 

The scientific community has been discussing for quite some time now the relationship between oxidative stress, defined as the imbalance between oxidant and antioxidants [45], and the health-disease status. An impressive amount of information available in the literature deals with the effects of the classic antioxidants, ascorbic acid, a-tocopherol, and jS-carotene in a huge series of pathophysiological situations in experimental animals and humans. Concerning the effects of the classic antioxidants on mitochondrial function in situations of oxidative stress, the information is not so vast and most of the time it is not conclusive. However, substantial progress has been made in the description of the mitochondrial alterations in neurodegenerative diseases and in the a-tocopherol effects,both as prevention and as treatment [46]. We will briefly review some reports related to vitamin E and mitochondrial dysfunction in oxidative metaboHc disorders and in the neurodegenerative Alzheimer s and Parkinson s diseases. 

In washed human platelets, NDGA inhibited the formation of 12-LOX products as well as the COX product 12-hydroxyheptadecatrienoic acid (12-HHT), with an IC50 of 5 pM, while boswellic acids (mixture of a- and P-isomers) at concentrations up to 400 pM exerted no effect. In addition, in a cell-free system, the non-enzymatic peroxidation of AA by iron (II)-ascorbate was not affected by boswellic acid at concentrations up to 400 pM, whereas NDGA abolished the peroxidation of AA in this test at a concentration of 10 pM. These results suggest that the activity of boswellic acids is selective in the 5-LOX pathway, and the mechanism of inhibition is different from that of the classic antioxidant 5-LOX inhibitors (NDGA, caffeic acid, quercetin) [96]. 

Classical antioxidants (AOs) like hindered phenols, Scheme 2, retard this transition metal promoted autoxidation process somewhat but give a very insufficient stabilization of powders or thin layers. However, by copolymerization with the so called "build-in" AOs, i.e. hindered phenols bearing 2-norbornene units like Ml - MS, the polymer stability could be improved. In addition, such compounds are very interesting AO s for the stabilization of other plastic substrates and rubbers [9]. AOs containing 2-norbornene units were also homo- and copolymerized to obtain polymeric stabilizers for plastics [10]. 

Over the past two decades attention has focused on the potential use of B vitamins in cardiovascular disease (CVD) prevention. Although classic antioxidant vitamins have failed to prevent vascular events in clinical trials, interest in B vitamins arose due to their homocysteine (Hey) lowering properties. Strong epidemiological and mechanistic evidence suggests that Hey is an independent cardiovascular risk factor (Antoniades et al. 2009a). In addition, this hypothesis confirms the original observation that patients with homocystinuria develop premature atherosclerosis and thromboembolic events early in life. 

The classical inhibition of oxidation processes is based on kinetic chain break and deactivation of branching, intermediate products. In the case of TP, chain type of the process is not obvious. The chain break in chemical increments suggests the inertness of residual inhibitor radical. These radicals are active above 200°C. Therefore, classical antioxidants are ineffective at high temperatures. 

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