Antioxidative activity mechanism

Probucol. Probucol is an antioxidant that is effective in lowering LDL cholesterol. Whereas probucol was known to lower cholesterol after relatively simple clinical trials (160), its mechanism of action as an antioxidant in the treatment of atherosclerosis is quite novel. Probucol has been shown to have the abiUty to produce regression of atherosclerotic lesions in animal models (161). Probucol therefore represents a novel class of pharmaceutical agent for the treatment of atherosclerosis. This effect occurs mechanistically, in part, by preventing oxidation of LDL, a necessary step in foam cell formation. This antioxidant activity has been shown in laboratory experiments and its activity in lowering LDL cholesterol in human studies is well documented (162). 

The electron transfer mechanism for antioxidant activity corresponding to eq. 16.5 makes the standard reduction potentials of interest for evaluation of antioxidative activity. The standard reduction potential of the phenoxyl radical of several flavonoids has been determined and forms the basis for correlation of rate of electron transfer for various oxidants from the flavonoid (Jovanovic etal., 1997 Jorgensen and Skibsted, 1998). The standard reduction potentials have also been used to establish antioxidant hierarchies. 

BONDET v, BRAND-wiLLiAMS w and BERSET c (1997) Kiuetics and mechanisms of antioxidant activity using the DPPH- free radical method, Lebensm Wiss Technol, 30, 609-15. 

Experimental evidence in humans is based upon intervention studies with diets enriched in carotenoids or carotenoid-contaiifing foods. Oxidative stress biomarkers are measured in plasma or urine. The inhibition of low density lipoprotein (LDL) oxidation has been posmlated as one mechanism by which antioxidants may prevent the development of atherosclerosis. Since carotenoids are transported mainly via LDL in blood, testing the susceptibility of carotenoid-loaded LDL to oxidation is a common method of evaluating the antioxidant activities of carotenoids in vivo. This type of smdy is more precisely of the ex vivo type because LDLs are extracted from plasma in order to be tested in vitro for oxidative sensitivity after the subjects are given a special diet. 

In atherosclerosis and other heart diseases, the role of carotenoids as antioxidants is probable, but for these types of diseases and also for other degenerative diseases such as cancers, non-antioxidant activities constitute other possible prevention mechanisms. These activities are, for example, stimulation of gap junction communications between cells, and the induction of detoxifying enzymes. The... 

In conclusion, oxidation of carotenoids by molecular oxygen, the so-called autoxidation process, is a complex phenomenon that is probably initiated by an external factor (radical, metal, etc.) and for which different mechanisms have been proposed. The autoxidation of a carotenoid is important to take into account when studying antioxidant activity because it can lower the apparent antioxidant activity of a carotenoid. ... 

Antioxidant capacities of common individual curcuminoids were determined in vitro by phosphomolybdenum and linoleic acid peroxidation methods. Antioxidant capacities expressed as ascorbic acid equivalents (pmol/g) were 3099 for curcumin, 2833 for demethoxycurcumin, and 2677 for bisdemethoxycurcumin at concentrations of 50 ppm. The same order of antioxidant activity (curcumin > demethoxycurcumin > bisdemethoxycurcumin) was observed when compared with BHT (buty-lated hydroxyl toluene) in linoleic peroxidation tests. The antioxidant activity of curcumin in the presence of ethyl linoleate was demonstrated and six reaction products were identified and structurally characterized. The mechanism proposed for this activity consisted of an oxidative coupling reaction at the 3 position of the curcumin with the lipid and a subsequent intramolecular Diels-Alder reaction. ... 

Antioxidant Activities of Synthetic Indole Derivatives and Possible Activity Mechanisms... 

Naturally occurring compounds such as phytochemicals, which possess anticar-cinogenic and other beneficial properties, are referred to as chemopreventers. One of the predominant mechanisms of their protective action is due to their antioxidant activity and the capacity to scavenge free radicals. Among the most investigated chemopreventers are some vitamins, plant polyphenols, and pigments such as carotenoids, chlorophylls, flavonoids, and betalains. Resolution of the potential protective roles of... 

UV-C technology is widely used as an alternative to chemical sterilization and microorganism reduction in food products (Lamikanra 2002 Fan and others 2008). Ultraviolet light also induces biological stress in plants and defense mechanisms in plant tissues with the consequent production of phytochemical compounds (Lee and Kader 2000). Phytoalexin accumulation could be accompanied by other inducible defenses such as cell-wall modifications, defense enzymes, and antioxidant activity, which have been reported with health benefits (Gonzalez-Aguilar and others 2007). It is well documented that UV-C irradiation has an effect in secondary metabolism. 

In 1989, we showed [142] that the Fe2+(rutin)2 complex is a more effective inhibitor than rutin of asbestos-induced erythrocyte hemolysis and asbestos-stimulated oxygen radical production by rat peritoneal macrophages. Later on, to evaluate the mechanisms of antioxidant activities of iron rutin and copper-rutin complexes, we compared the effects of these complexes on iron-dependent liposomal and microsomal lipid peroxidation [165], It was found that the iron rutin complex was by two to three times a more efficient inhibitor of liposomal peroxidation than the copper-rutin complex, while the opposite tendency was observed in NADPH-dependent microsomal peroxidation. On the other hand, the copper rutin complex was much more effective than the iron rutin complex in the suppression of microsomal superoxide production, indicating that the copper rutin complex indeed acquired additional SOD-dismuting activity because superoxide is an initiator of NADPH-dependent... 

Since glutathione is synthesized in cells in relatively huge amounts, it is seldom applied as pharmacological antioxidant. Furthermore, the mechanism of its antioxidant activity is not so simple as that of vitamins E and C. The major reason is that the GS radical formed during scavenging of free radicals by GSH does not disappear by dimerization but participates in the chain reaction, producing superoxide (Reactions (20)-(23)). Furthermore, it has recently been shown that contrary to previous findings the rate constant for the reaction of GSH with superoxide is relatively small (200-1000 lmol-1 s-1) [211,223],... 

Very interesting mechanism of the enhanced glutathione antioxidant activity in the presence of SOD was offered by Winterbourn [227]. She pointed out that the interaction of all free radicals with glutathione resulted in the formation of superoxide as the only final active species a free radical sink. Therefore, the mixture of glutathione together with SOD may be considered as a universal scavenger of free radicals of any structure. 

As already mentioned, another mechanism of antioxidant activity of ubiquinones is scavenging of free radicals by ubihydroquinones (Reaction (26)) ... 

Regarding the proposed mechanisms of carvedilol antioxidative activity, membrane stabilization through the biophysical interaction of carvedilol with the membrane seems to be the most reliable one. However, a higher antioxidant activity of the metabolite SB 211475 leads to another explanation. In contrast to the parent carvedilol, SB 211475 has the active free radical scavenging phenolic hydroxyl, which is apparently responsible for its enhanced antioxidant activity. Thus, we may suggest that the in vivo antioxidant activity of carvedilol is due to its converting into active metabolites, which, for example, may be formed in the reactions with primary free radicals such as hydroxyl radicals. 

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... 

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. 

Metallothioneins (MT) are unique 7-kDa proteins containing 20 cysteine molecules bounded to seven zinc atoms, which form two clusters with bridging or terminal cysteine thiolates. A main function of MT is to serve as a source for the distribution of zinc in cells, and this function is connected with the MT redox activity, which is responsible for the regulation of binding and release of zinc. It has been shown that the release of zinc is stimulated by MT oxidation in the reaction with glutathione disulfide or other biological disulfides [334]. MT redox properties led to a suggestion that MT may possesses antioxidant activity. The mechanism of MT antioxidant activity is of a special interest in connection with the possible antioxidant effects of zinc. (Zinc can be substituted in MT by some other metals such as copper or cadmium, but Ca MT and Cu MT exhibit manly prooxidant activity.)... 

Despite the conclusions in the cited literature about direct MT interaction with free radicals, the mechanism of MT antioxidant activity remains obscure. Markant and Pallauf [339] concluded that cysteine groups and not zinc are responsible for the inhibition of lipid peroxidation in hepatocytes. Maret and Vallee [340,341] also questioned the possibility of direct scavenging of free radicals by MT and suggested that zinc release is a major mechanism of antioxidant effects of metallothioneins. 

Thus, the mechanism of MT antioxidant activity might be connected with the possible antioxidant effect of zinc. Zinc is a nontransition metal and therefore, its participation in redox processes is not really expected. The simplest mechanism of zinc antioxidant activity is the competition with transition metal ions capable of initiating free radical-mediated processes. For example, it has recently been shown [342] that zinc inhibited copper- and iron-initiated liposomal peroxidation but had no effect on peroxidative processes initiated by free radicals and peroxynitrite. These findings contradict the earlier results obtained by Coassin et al. [343] who found no inhibitory effects of zinc on microsomal lipid peroxidation in contrast to the inhibitory effects of manganese and cobalt. Yeomans et al. [344] showed that the zinc-histidine complex is able to inhibit copper-induced LDL oxidation, but the antioxidant effect of this complex obviously depended on histidine and not zinc because zinc sulfate was ineffective. We proposed another mode of possible antioxidant effect of zinc [345], It has been found that Zn and Mg aspartates inhibited oxygen radical production by xanthine oxidase, NADPH oxidase, and human blood leukocytes. The antioxidant effect of these salts supposedly was a consequence of the acceleration of spontaneous superoxide dismutation due to increasing medium acidity. 

Cannabidiol and THC reduced neurotoxicty induced by glutamate in cortical neurons (Hampson et al. 1998). This result was effective for toxicity induced at both NMDA and AMPA/kainate receptors, and was independent of cannabinoid receptor activity. The mechanism of neuroprotection appears to be by their potent antioxidant activity. They were even more protective against glutamate neurotoxicity than either ascorbate or o-tocopherol. 

Benzoxathiins, considered as 4-thiaflavans, have shown antimicrobial <2004MI317> and antioxidant activity and seem to operate by both the flavonoid-like and the tocopherol-like mechanisms <2001CC551, 20050BC3066>. 

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