Synergism, antioxidants

In antioxidants, synergism appears to arise either from one antioxidant effectively regenerating another so that the latter does not become consumed or by the two antioxidants functioning by differing mechanisms. The latter is more important and it is easy to see how effective a combination of peroxide decomposer and chain-breaking antioxidant can be. 

Two final points should be made while considering antioxidant synergism. Firstly, some antioxidants which function by more than one mechanism are in all probability autosynergistic. Secondly, certain additives which appear to act... 

Graversen HB, Becker EM, Skibsted LH and Andersen ML. 2008. Antioxidant synergism between fruit juice and a-tocopherol. A comparison between high phenolic black chokeberry (Aronia melanocarpa) and high ascorbic blackcurrant (Ribes nigrum). Eur Food Res Technol 226(4) 737-743. 

Synergism implies that two-component antioxidants act differently during inhibition. Moreover, in a given mixture of antioxidants, synergism may arise from more than one cause—e.g., a combination of an inhibitor of free radicals with a synergist that can decompose peroxides and can also donate hydrogen (12). The mechanisms most supported in the literature are presented below. 

Nunuz-Delicado, E. Sanchez-Ferrer, A. Garcia-Carmona, F. Cyclodextrins as secondary antioxidants synergism with ascorbic acid. J. Agric. Food Chem. 1997, 45 (8), 2830-2835. 

The ascorbic acid-vitamin E interaction is also important to maintain the protease-antiprotease balance in the lung. Ascorbic acid reacts with glutathione, and through antioxidant synergism it can increase the effectiveness of vitamin E. The following series of enzymatic reduction reactions that occur in the cells illustrates the participation of ascorbic acid in the inhibition of lipid peroxidation. 

Dai, R, Chen, W.-F. Zhou B. (2008). Antioxidant synergism of green tea polyphenols with a-tocopherol and L-ascorbic acid in SDS micelles. Biochimie, 90,1499-1505. 

Although aminyl radicals are stable towards oxygen, they can oxidi2e other aromatic amines, phenols and thiols (10), and regenerate the diarylamine. Thus, mixtures of phenols and diarylamines frequendy show better antioxidant activity than either one alone. This is called synergism. 

Antioxidants are today often used in combination. One reason for this is that certain combinations can exhibit in a polymer an effect sometimes found with other additives, that known as synergism. In these circumstances two antioxidants may exhibit a co-operative effect and be more powerful than either antioxidant used alone, even when the total antioxidant concentration is the same. Certain terms are sometimes encountered here and these are defined in Table 7.6. 

Figure 7.7. The synergism of sulphur antioxidants with carbon black as constrasted to the adverse effect shown with conventional antioxidants (in polyethylene)...

When two antioxidants are used together, a synergistic improvement in activity usually results. Synergism can arise from three combinations (1) homosynergism — two chemically similar antioxidants (for instance, two hindered phenols) (2) autosynergism — two different antioxidants functions that are present in the same molecule (3) heterosynergism — the cooperative effect between mechanistically different classes of antioxidants, such as the combined effect of primary and secondary antioxidants. Thus, combinations of phenols and phosphites are widely used to stabilize synthetic rubbers. 

A cooperative interaction between two or more antioxidants (or antioxidant function) that leads to an overall antioxidant effect greater than the sum of the individual effects of each antioxidant is referred to as synergism. Synergism can be achieved in different ways. It may arise from the combined action of two chemically similar antioxidants, e.g., two hindered phenols (homosynergism), or when two different antioxidant functions are present in the same molecule (autosynergism) the latter is exemplified by many commercial antioxidants (e.g., Irgastab 2002, AO 29 Table lb), which have CB and UVA activity. 

Synergism can also arise from cooperative effects between mechanistically different classes of antioxidants, e.g., the chain breaking antioxidants and peroxide decomposers (heterosynergism) [42]. For example, the synergism between hindered phenols (CB—D) and phosphites or sulphides (PD) is particularly important in thermal oxidation (Table 2). Similarly, effective synergism is achieved between metal dithiolates (PD) and UV-ab-sorbers (e.g., UV 531), as well as between HALS and UV-absorbers, (Table 3). 

Figure 45-6. Interaction and synergism between antioxidant systems operating in the lipid phase (membranes) of the cell and the aqueous phase (cytosol). (R-,free radical PUFA-00-, peroxyl free radical of polyunsaturated fatty acid in membrane phospholipid PUFA-OOH, hydroperoxy polyunsaturated fatty acid in membrane phospholipid released as hydroperoxy free fatty acid into cytosol by the action of phospholipase Aj PUFA-OH, hydroxy polyunsaturated fatty acid TocOH, vitamin E (a-tocopherol) TocO, free radical of a-tocopherol Se, selenium GSH, reduced glutathione GS-SG, oxidized glutathione, which is returned to the reduced state after reaction with NADPH catalyzed by glutathione reductase PUFA-H, polyunsaturated fatty acid.)...

The most common natural antioxidants are tocopherols, ascorbic acid and P-carotene (more often synthetic nature-identical compounds than natural products). Their changes were studied in detail in model systems, fats and oils, but experimental evidence is mainly lacking on more complicated systems, such as natural foods and ready dishes. Still less is known on different antioxidants from spices and from essential oils. These data will probably be obtained gradually. Very little is known about synergism of antioxidants in food products other than edible fats and oils or their regeneration from the respective free radicals and quinones. In mixtures, some antioxidants are preferentially destroyed and others are saved. Some data have already been published, but these complex changes should be studied in more detail. 

Hence, for both of the oxidants, N02 and ONOO-, a marked synergism in cell protection by the antioxidant combination of P-CAR with vitamins E and C was observed for both in vivo and in vitro experiments, although the synergistic effect was more pronounced in protection from N02 . 

Anti-oxidants can be divided into two classes depending on which part of the radical chain they quench. Primary anti-oxidants are radical scavengers and will react with alkyl chain radicals (R ) or hydroperoxides (ROOH). Secondary antioxidants work in combination with primary anti-oxidants and principally act by converting peroxide radicals (ROO ) into non-radical stable products. Synergism often works when both classes are used together. 

Synergism based on the mixture of a chain-breaking antioxidant (sterically hindered phenol) and a hydroperoxide decomposer (organic sulfides or phosphites). 

Tomato was reported to exert antioxidant activity in some studies (Vinson and others 1998 Kahkonen and others 1999), whereas it showed no antioxidant activity or even acted as a pro-oxidant in others (Gazzani and others 1998). The antioxidant effect of tomato is most probably due to synergism between several compounds and not due to lycopene content alone, as pure lycopene and several other carotenoids act as pro-oxidants in a lipid environment (Al-Saikhan and others 1995 Haila and others 1996). 

Synergism of Chain Termination and Hydroperoxide Decomposing the Antioxidants... 

For initiated oxidation, the inhibitory criterion could be defined as the ratio v0/v or (v0/ v — v/v0), where v0 and v are the rates of initiated oxidation in the absence and presence of the fixed concentration of an inhibitor, respectively. Another criterion could be defined as the ratio of the inhibition coefficient of the combined action of a few antioxidants / to the sum of the inhibition coefficients of individual antioxidants when the conditions of oxidation are fixed (fx = IfiXi where f, and x, are the inhibition coefficient and molar fraction of z th antioxidant terminating the chain). It should, however, be noted that synergism during initiated oxidation seldom takes place and is typical of autoxidation, where the main source of radicals is formed hydroperoxide. It is virtually impossible to measure the initial rate in the presence of inhibitors in such experiments. Hence, inhibitory effects of individual inhibitors and their mixtures are usually evaluated from the duration of retardation (induction period), which equals the span of time elapsed from the onset of experiment to the moment of consumption of a certain amount of oxygen or attainment of a certain, well-measurable rate of oxidation. Then three aforementioned cases of autoxidation response to inhibitors can be described by the following inequalities (r is the induction period of a mixture of antioxidants). 

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