Nitric oxide antioxidant effects

Hydroxyurea is a ribonucleotide reductase inhibitor that prevents DNA synthesis and traditionally has been used in chemotherapy regimens. Studies in the 1990s also found that hydroxyurea increases HbF levels as well as increasing the number of HbF-containing reticulocytes and intracellular HbF. Other beneficial effects of hydroxyurea include antioxidant properties, reduction of neutrophils and monocytes, increased intracellular water content leading to increased red cell deformability, decreased red cell adhesion to endothelium, and increased levels of nitric oxide, which is a regulator involved in physiologic disturbances.22... 

Bor JY, Chen HY and Yen GC. 2006. Evaluation of antioxidant activity and inhibitory effect on nitric oxide production of some common vegetables. J Agric Food Chem 54(5) 1680-1686. 

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. 

Belkner et al. [32] demonstrated that 15-LOX oxidized preferably LDL cholesterol esters. Even in the presence of free linoleic acid, cholesteryl linoleate continued to be a major LOX substrate. It was also found that the depletion of LDL from a-tocopherol has not prevented the LDL oxidation. This is of a special interest in connection with the role of a-tocopherol in LDL oxidation. As the majority of cholesteryl esters is normally buried in the core of a lipoprotein particle and cannot be directly oxidized by LOX, it has been suggested that LDL oxidation might be initiated by a-tocopheryl radical formed during the oxidation of a-tocopherol [33,34]. Correspondingly, it was concluded that the oxidation of LDL by soybean and recombinant human 15-LOXs may occur by two pathways (a) LDL-free fatty acids are oxidized enzymatically with the formation of a-tocopheryl radical, and (b) the a-tocopheryl-mediated oxidation of cholesteryl esters occurs via a nonenzymatic way. Pro and con proofs related to the prooxidant role of a-tocopherol were considered in Chapter 25 in connection with the study of nonenzymatic lipid oxidation and in Chapter 29 dedicated to antioxidants. It should be stressed that comparison of the possible effects of a-tocopherol and nitric oxide on LDL oxidation does not support importance of a-tocopherol prooxidant activity. It should be mentioned that the above data describing the activity of cholesteryl esters in LDL oxidation are in contradiction with some earlier results. Thus in 1988, Sparrow et al. [35] suggested that the 15-LOX-catalyzed oxidation of LDL is accelerated in the presence of phospholipase A2, i.e., the hydrolysis of cholesterol esters is an important step in LDL oxidation. 

In 1986, the antioxidant effects of thioredoxin reductase were studied by Schallreuter et al. [81]. It has been shown that thioredoxin reductase was contained in the plasma membrane surface of human keratinocytes where it provided skin protection against free radical mediated damage. Later on, the reductive activity of Trx/thioredoxin reductase system has been shown for the reduction of ascorbyl radical to ascorbate [82], the redox regulation of NFkB factor [83], and in the regulation of nitric oxide-nitric oxide synthase activities [84,85],... 

Kanner, J., Harel, S., Shagalovich, J., and Berman, S. (1984). Antioxidative effect of nitrite in cured meat pnxlucts Nitric oxide-iron complexes of low molecular weight. ]. Agric. Food Chem. 32, 512-515. 

Hogg, N. Pro-oxidant and antioxidant effects of nitric oxide, Analysis of Free Radicals in Biological Systems Eds. Favier, A. E. Cadet, J. Kalyanaraman, B. Fontecave, M. Pierre, J.-L. Birkhauser Verlag Basel, 1995, pp. 37-49. 

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