Prooxidative effect

The activity of antioxidants reverses under certain conditions they become prooxidants. One way in which a-tocopherol can become perox-idatively active is shown in Formula 3.81. Another way is through the formation of the chro-manoxyl radical in concentrations high enough to overcome the inertness mentioned in 3.7.3.1 and abstract H-atoms from unsaturated acyl lipids to a definite extent, starting lipid peroxidation. This activity reversion, which is also undesirable from a nutritional and physiological point of 

In the presence of heavy metal ions, e.g., Fe , ascorbic acid becomes a peroxidant. It reduces Fe to Fe , which can produce superoxide radical anions or hydroxyl radicals with oxygen or H2O2 Fenton reaction, cf. 3.7.2.1.8) Prooxidative effects have also been observed with carotenoids and flavonoids at higher concentrations. 

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Where there is a danger of contamination of a hydrocarbon polymer with such ions it is common practice to use a chelating agent which forms a complex with the metal. It is, however, important to stress that a chelating agent which effectively slows down oxidation initiated by one metal ion may have a prooxidant effect with another metal ion. Table 7.5 summarises some work by... 

A molecule that has a prooxidant effect can be dehned as a molecule that can react with reactive oxygen species (ROS) to form compounds more deleterious to biomolecules than the ROS alone. Possible prooxidant activity of carotenoids was for the first time mentioned by Burton and Ingold. Since then, many other examples of loss of antioxidant activity or prooxidant activity have been illustrated and reviewed in the literature. Increasing oxygen partial pressure (PO2) and/or carotenoid concentration can convert a carotenoid from antioxidant to prooxidant. Thus, depending on the environment, the same molecule can exert either antioxidant or prooxidant activity. ... 

Various types of cell-based in vitro studies have shown that carotenoids can exert prooxidant effects under certain conditions. Most of these studies show in fact decreases in antioxidant efficacy of carotenoids with increasing carotenoid concentration examples of true prooxidant effects are rarer. It is also important to pay attention to the experimental conditions and their biological relevance. Indeed, carotenoids have sometimes been proven to (I) exert prooxidant activity in an atmosphere of pure oxygen, (2) never occur in vivo, or (3) appear in concentrations that they would never reach in vivo. 

Bowry, V.W. and Stocker, R. (1993). Tocopherol-mediated peroxidation. The prooxidant effect of vitamin E on the radical-initiated oxidation of human low-density lipoprotein. J. Am. Chem. Soc. 115, 6029-6044. 

It has been found (Polyakov et al. 2001c) that when carotenoids are involved in a reaction cycle with the participation of iron as Fe2+, an increase of the total radical yield or a prooxidant effect will occur and will increase with decreasing carotenoid oxidation potential and its scavenging activity. The mechanism of the participating carotenoid is shown in Scheme 9.4 (Polyakov et al. 2001c). 

Vitamin C is also an antioxidant (supplements over 500 mg per day may have prooxidant effect). 

Thus the competition between stimulatory and inhibitory effects of NO depends on the competition between two mechanisms the direct interaction of NO with free radicals formed in lipid peroxidation and the conversion of NO into peroxynitrite or other reactive NO metabolites. Based on this suggestion, Freeman and his coworkers [42-44] concluded that the prooxidant and antioxidant properties of nitric oxide depend on the relative concentrations of NO and oxygen. It was supposed that the prooxidant effect of nitric oxide originated from its reaction with dioxygen and superoxide ... 

As mentioned earlier, ascorbate and ubihydroquinone regenerate a-tocopherol contained in a LDL particle and by this may enhance its antioxidant activity. Stocker and his coworkers [123] suggest that this role of ubihydroquinone is especially important. However, it is questionable because ubihydroquinone content in LDL is very small and only 50% to 60% of LDL particles contain a molecule of ubihydroquinone. Moreover, there is another apparently much more effective co-antioxidant of a-tocopherol in LDL particles, namely, nitric oxide [125], It has been already mentioned that nitric oxide exhibits both antioxidant and prooxidant effects depending on the 02 /NO ratio [42]. It is important that NO concentrates up to 25-fold in lipid membranes and LDL compartments due to the high lipid partition coefficient, charge neutrality, and small molecular radius [126,127]. Because of this, the value of 02 /N0 ratio should be very small, and the antioxidant effect of NO must exceed the prooxidant effect of peroxynitrite. As the rate constants for the recombination reaction of NO with peroxyl radicals are close to diffusion limit (about 109 1 mol 1 s 1 [125]), NO will inhibit both Reactions (7) and (8) and by that spare a-tocopherol in LDL oxidation. 

It has been already pointed out that nitric oxide exhibits antioxidant effect in LDL oxidation at the NO/ 02 ratio 1. Under these conditions the antioxidant effect of NO prevails on the prooxidant effect of peroxynitrite. Although some earlier studies suggested the possibility of NO-mediated LDL oxidation [152,153], these findings were not confirmed [154]. On the other hand, at lower values of N0/02 ratio the formed peroxynitrite becomes an efficient initiator of LDL modification. Beckman et al. [155] suggested that peroxynitrite rapidly reacts with tyrosine residues to form 3-nitrotyrosine. Later on, Leeuwenburgh et al. [156] found that 3-nitrotyrosine was formed in the reaction of peroxynitrite with LDL. The level of 3-nitrotyrosine sharply differed for healthy subjects and patients with cardiovascular diseases LDL isolated from the plasma of healthy subjects contained a very low level of 3-nitrotyrosine (9 + 7 pmol/mol 1 of tyrosine), while LDL isolated from aortic atherosclerotic intima had a 90-fold higher level (840 + 140 pmol/moD1 of tyrosine). It has been proposed that peroxynitrite formed in the human artery wall is able to promote LDL oxidation in vivo. 

HOCl-mediated protein oxidation accelerates under pathophysiological conditions. Thus, proteins from extracellular matrix obtained from advanced human atherosclerotic lesions contained the enhanced levels of oxidized amino acids (DOPA and dityrosine) compared to healthy arterial tissue [44], It was also found that superoxide enhanced the prooxidant effect of hypochlorite in protein oxidation supposedly by the decomposition of chloramines and chlor-amides forming nitrogen-centered free radicals and increasing protein fragmentation [45], In addition to chlorination, hypochlorite is able to oxidize proteins. The most readily oxidized amino acid residue of protein is methionine. Methionine is reversibly oxidized by many oxidants including hypochlorite to methionine sulfide and irreversibly to methionine sulfone [46] ... 

The possible prooxidant effects of a major lipophilic antioxidant vitamin E (a-tocopherol) have already been discussed in Chapter 25. Yamashita et al. [82] showed that a-tocopherol induced extensive DNA damage including base modification and strand breakage in the... 

The mechanism of prooxidant effect of a-tocopherol in aqueous lipid dispersions such as LDLs has been studied [22], This so-called tocopherol-mediated peroxidation is considered in detail in Chapter 25, however, in this chapter we should like to return once more to the question of possible prooxidant activity of vitamin E. The antioxidant effect of a-tocopherol on lipid peroxidation including LDL oxidation is well established in both in vitro and in vivo systems (see, for example, Refs. [3,4] and many other references throughout this book). However, Ingold et al. [22] suggested that despite its undoubted high antioxidant efficiency in homogenous solution a-tocopherol can become a chain transfer agent in aqueous LDL... 

Recently, Carr and Frei reviewed studies on the antioxidant and prooxidant effects of ascorbic acid [8]. These authors pointed out that a highly controversial work by Podmore and coworkers [71] who found that the prooxidant effect of ascorbic acid supplementation to healthy volunteers is much questionable. These authors demonstrated that of the 44 in vivo studies, 38 showed the antioxidant effect of ascorbic acid, 14 showed no change, and only six showed the enhancement of oxidative damage after ascorbate supplementation. It was concluded that ascorbic acid is an antioxidant in biological fluids, animals, and humans, both with and without iron supplementation. 

Cytotoxic prooxidant effects of flavonoids can also be a consequence of their enzymatic oxidation. For example, it was found that quercetin was oxidized by lactate peroxide to form semiquinone and quinone [181]. 

Regeneration of superoxide during the oxidation of thiols hints at the possible prooxidant effect of these antioxidants. This suggestion was recently confirmed by Mottley and Mason [212] who have showed that superoxide was formed in the oxidation of DHLA by horseradish peroxidase in the presence of phenol. However, DHLA is dithiolic compound and the other mechanisms such as the concerted mechanism, which has been proposed earlier for flavonoids may be realized (Figure 29.6). 

This mechanism is now considered to be of importance for the protection of LDL against oxidation stress, Chapter 25.) The antioxidant effect of ubiquinones on lipid peroxidation was first shown in 1980 [237]. In 1987 Solaini et al. [238] showed that the depletion of beef heart mitochondria from ubiquinone enhanced the iron adriamycin-initiated lipid peroxidation whereas the reincorporation of ubiquinone in mitochondria depressed lipid peroxidation. It was concluded that ubiquinone is able to protect mitochondria against the prooxidant effect of adriamycin. Inhibition of in vitro and in vivo liposomal, microsomal, and mitochondrial lipid peroxidation has also been shown in studies by Beyer [239] and Frei et al. [240]. Later on, it was suggested that ubihydroquinones inhibit lipid peroxidation only in cooperation with vitamin E [241]. However, simultaneous presence of ubihydroquinone and vitamin E apparently is not always necessary [242], although the synergistic interaction of these antioxidants may take place (see below). It has been shown that the enzymatic reduction of ubiquinones to ubihydroquinones is catalyzed by NADH-dependent plasma membrane reductase and NADPH-dependent cytosolic ubiquinone reductase [243,244]. 

In 1998, Schlotte et al. [259] showed that uric acid inhibited LDL oxidation. However, subsequent studies showed that in the case of copper-initiated LDL oxidation uric acid behaves itself as prooxidant [260,261]. It has been suggested that in this case uric acid enhances LDL oxidation by the reduction of cupric into cuprous ions and that the prooxidant effect of uric acid may be prevented by ascorbate. On the other hand, urate radicals formed during the interaction of uric acid with peroxyl radicals are able to react with other compounds, for example, flavonoids [262], and by that participate in the propagation of free radical damaging reactions. In addition to the inhibition of oxygen radical-mediated processes, uric acid is an effective scavenger of peroxynitrite [263]. 

It is well known that most of the antioxidant enzymes and substrates can exhibit prooxidant activity under certain conditions, mainly because many stages of the reactions catalyzed by such enzymes are reversible. The question of possible prooxidant effects of SODs and the ability of SODs to react with the other substrates than superoxide have been studied for a long time. It is known that CuZnSOD is inactivated by the hydrogen peroxide formed. Hodgson and Fridovich [3] proposed that this inactivation depends on the reaction of hydrogen peroxide with the oxidized form Cu(II)ZnSOD yielding the bound hydroxyl radicals. 

Another mode of SOD prooxidant activity has been proposed by Offer et al. [9]. In 1973, Rotilio et al. [10] showed that SOD can readily oxidize ferrocyanide. Offer et al. [9] found that low SOD concentrations inhibited superoxide-induced oxidation of ferrocyanide, but SOD becomes prooxidative at higher concentrations. As this reaction did not require hydrogen peroxide, it was suggested that the prooxidant effect of enhanced SOD concentrations might be explained by decreasing the steady state of superoxide and the direct oxidation of ferrocyanide by SOD. 

Sanders et al. [133] found that although quercetin treatment of streptozotocin diabetic rats diminished oxidized glutathione in brain and hepatic glutathione peroxidase activity, this flavonoid enhanced hepatic lipid peroxidation, decreased hepatic glutathione level, and increased renal and cardiac glutathione peroxidase activity. In authors opinion the partial prooxidant effect of quercetin questions the efficacy of quercetin therapy in diabetic patients. (Antioxidant and prooxidant activities of flavonoids are discussed in Chapter 29.) Administration of endothelin antagonist J-104132 to streptozotocin-induced diabetic rats inhibited the enhanced endothelin-1-stimulated superoxide production [134]. Interleukin-10 preserved endothelium-dependent vasorelaxation in streptozotocin-induced diabetic mice probably by reducing superoxide production by xanthine oxidase [135]. 

Pronzato MA, Domenicotti C, Biasi F, et al. 1990. Inactivation of hepatocyte protein kinase C by carbon tetrachloride involvement of drug s metabolic activation and prooxidant effect. Biochem Biophys Res Commun 171 1353-1360. 

AIBN is, however, virtually unaffected by the presence of dithio-phosphates (Table II). Further, with specific reference to the oxidation of the disulfide in Table I, which has no effect on the rate of AIBN-initi-ated autoxidation of cumene (6), it is unlikely that the efficiency of radical production from AIBN increases since this would produce a prooxidant effect in cumene. Thus, the zinc salt inhibitor is being oxidized in competition with the main chain reaction. 

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