Lipids nonenzymatic

The acetylene aminopyrazole 103 was capable of inhibiting the processes of lipid peroxidation both in the enzymatic and nonenzymatic peroxidation system (76MI2). Finally, 4-[3-(l-methyl-l//-pyrazol-3-yl)-prop-2-ynyl]morpholine hydrochloride 104 was patented as a compound with high hypoxic activity (93MIP1). 

Both enzymatic and nonenzymatic biotransformation of acrylonitrile occurs. Acrylonitrile is capable of covalently binding to proteins and other macromolecules such as lipids or nucleic acids, or acrylonitrile can also be directly conjugated to glutathione and excreted in urine as cyanoethylmercapturic acid. 

Lipid peroxidation may proceed by both enzymatic and nonenzymatic pathways. Enzymatic peroxidation is catalyzed by enzymes such as lipoxygenases and cyclooxygenases (COXs) and is considered in Chapter 26. One of the most important questions in the study of the mechanisms of lipid peroxidation is the characteristic of an initiation stage. Obvious... 

Thus, the formation of isoprostanes is rightly considered as a unique noninvasive method for the estimation of in vivo lipid peroxidation. However, the use of 8-Ao-PGF2a isoprostane (now known as iPF2a-III) as an index of nonenzymatic in vivo peroxidation has some limitations due to the possibility of its formation by COX-1- and COX-2-catalyzed... 

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. 

The expression of 15-LOX in atherosclerotic lesions is one of the major causes of LDL oxidative modification during atherosclerosis. To obtain the experimental evidence of a principal role of 15-LOX in atherosclerosis under in vivo conditions, Kuhn et al. [67] studied the structure of oxidized LDL isolated from the aorta of rabbits fed with a cholesterol-rich diet. It was found that specific LOX products were present in early atherosclerotic lesions. On the later stages of atherosclerosis the content of these products diminished while the amount of products originating from nonenzymatic lipid peroxidation increased. It was concluded that arachidonate 15-LOX is of pathophysiological importance at the early stages of atherosclerosis. Folcik et al. [68] demonstrated that 15-LOX contributed to the oxidation of LDL in human atherosclerotic plaques because they observed an increase in the stereospecificity of oxidation in oxidized products. Arachidonate 15-LOX is apparently more active in young human lesions and therefore, may be of pathophysiological importance for earlier atherosclerosis. In advanced human plaques nonenzymatic lipid peroxidation products prevailed [69],... 

Similar to lipids the oxidation of proteins has already been studied for more than 20 years. Before discussing the data on protein oxidation, it should be mentioned that many associated questions were already considered in previous chapters. For example, the oxidation of lipoproteins, which is closely connected with the problems of nonenzymatic lipid peroxidation was discussed in Chapter 25. Many questions on the interaction of superoxide and nitric oxide with enzymes including the inhibition of enzymatic activities of prooxidant and antioxidant enzymes are considered in Chapters 22 and 30. Therefore, the findings reported in those chapters should be taken into account for considering the data presented in this chapter. 

Cystic fibrosis is the most common lethal autosomal-recessive disease, in which oxidative stress takes place at the airway surface [274]. This disease is characterized by chronic infection and inflammation. Enhanced free radical formation in cystic fibrosis has been shown as early as 1989 [275] and was confirmed in many following studies (see references in Ref. [274]). Contemporary studies also confirm the importance of oxidative stress in the development of cystic fibrosis. Ciabattoni et al. [276] demonstrated the enhanced in vivo lipid peroxidation and platelet activation in this disease. These authors found that urinary excretion of the products of nonenzymatic lipid peroxidation PGF2 and TXB2 was significantly higher in cystic fibrotic patients than in control subjects. It is of importance that vitamin E supplementation resulted in the reduction of the levels of these products of peroxidation. Exhaled ethane, a noninvasive marker of oxidative stress, has also been shown to increase in cystic fibrosis patients [277]. 

Lipids can be oxidized by some ROS such as hydroxyl ( OH). but not by H202, NO, or 02 - (Halliwell and Gutteridge 1999). However, both enzymatic and nonenzymatic cellular mechanisms can oxidize fatty acids. Challenging L. digitata sporophytes with lipopolysaccharides from various sources resulted in a rapid release of free fatty acids (FFAs) with a concomitant accumulation of oxidized derivatives of linolenic (08 2) and eicosapentaenoic acid (C20 5) (Kiipper et al. 2006). Other strong inducers of the oxidative burst, such as oligoguluronates, in Laminaria could induce neither the release of FFAs nor the oxylipin production. These results... 

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