Cholesterol oxidation, initiation

As mentioned earlier, oxidation of LDL is initiated by free radical attack at the diallylic positions of unsaturated fatty acids. For example, copper- or endothelial cell-initiated LDL oxidation resulted in a large formation of monohydroxy derivatives of linoleic and arachi-donic acids at the early stage of the reaction [175], During the reaction, the amount of these products is diminished, and monohydroxy derivatives of oleic acid appeared. Thus, monohydroxy derivatives of unsaturated acids are the major products of the oxidation of human LDL. Breuer et al. [176] measured cholesterol oxidation products (oxysterols) formed during copper- or soybean lipoxygenase-initiated LDL oxidation. They identified chlolcst-5-cnc-3(3, 4a-diol, cholest-5-ene-3(3, 4(3-diol, and cholestane-3 3, 5a, 6a-triol, which are present in human atherosclerotic plaques. 

Nielsen, J.H., Olsen, C.E., Skibsted, L.H. 1996a. Cholesterol oxidation in a heterogeneous system initiated by water-soluble radicals. Food Chem. 56, 33-37. 

The synthesis of manganese acetate tetra-p-aminophenylporphyrinate (MnAc-TAPhP) chemically immobilized on different polymeric supports was carried out, and its catalytic activity during cholesterol oxidation by molecular oxygen was studied [107]. Soluble porphyrin-containing polymers were obtained by copolymerization of methacrylate or 4-vinylpyridine with the product of interaction of acrylic acid chloride with MnAcTAPhP. Cholesterol oxidation was performed in a 1 1 mixture of ethanol and chloroform. The effective rate constants, / eff, were determined from the initial rate of product formation. 

Cholesterol Oxidation Products in the Initiation, Progression, and Fate of Atherosclerotic Lesions... 

Another important finding is that mmLDL contains mainly phospholipid oxidation products, while the oxysterol content increases proportionally with the oxidation rate (Shentu et al. 2012). Taken together, these very recent experimental reports and reviews suggest a primary role for oxysterols in the progression of atherosclerosis, rather than in its initiation. However, the marked biochemical changes that oxysterols have been found to bring about in endothelial cells (ECs) suggest that the possibility that cholesterol oxides make some contribution to endothelial dysfunction in atherosclerosis should not be discarded a priori. 

With regard to the involvement of cholesterol oxides in the initiation of atherosclerotic lesions, the current state of research indicates that they can indeed modnlate endothelial dysfunction and that their pro-inflammatory effects appear to be prominent in atherosclerotic-prone areas of the arterial tree. 

The natural occurrence of 24,25- and 25,26-dihydroxyvitamin D metabolites has led to studies of their synthesis and configurational assignment via the initial preparation of the correspondingly substituted cholesterol derivatives. Initial approaches to these compounds were carried out on oxidized forms of A24- or A25-steroids (98, 142, 154, 155, 169, 170) or by reduction of the ketol (46) (5i). In these cases, almost equal amounts of the diasteroisomeric epoxides or diols were obtained because the newly formed asymmetric position was too distant from a chiral center (i. e., at C-17 or C-20) for stereoselective induction. 

A voluminous literature has been published on a wide range of oxidation products of cholesterol because of their potential adverse effects on health and in compromising the safety of various food products (Chapters 12 and 13). This section is limited to the initial hydroperoxides serving as precursors to a complex mixture of oxygenated products, also referred to either as oxysterols or as cholesterol oxides. These products formed either enzymatically or non-enzymatically in biological and food systems will be discussed fiuther in Chapters 11 to 13. 

The hydroperoxides produced by oxygen attack at the aUyhc 7-position of cholesterol have been identified in low-density hpoprotein (LDL), oxidized in vitro, rat skin, marine animals and plant tissues. Cholesterol oxidation in solution or in aqueous dispersions is initiated by hydrogen abstraction to... 

The rare example of synergistic action of a binary mixture of 1-naphthyl-A-phcnylaminc and phenol (1-naphthol, 2-(l,l-dimethylethyl)hydroquinone) on the initiated oxidation of cholesterol esters was evidenced by Vardanyan [34]. The mixture of two antioxidants was proved to terminate more chains than both inhibitors can do separately ( > /[xj). For example, 1-naphtol in a concentration of 5 x 10 5 mol L-1 creates the induction period t=170s, 1 -naphthyl-A-phenylamine in a concentration of 1.0 x 10-4 mol L 1 creates the induction period t = 400s, and together both antioxidants create the induction period r = 770 s (oxidation of ester of pelargonic acid cholesterol at 7= 348 K with AIBN as initiator). Hence, the ratio fs/ZfjXi was found equal to 2.78. The formation of an efficient intermediate inhibitor as a result of interaction of intermediate free radicals formed from phenol and amine was postulated. This inhibitor was proved to be produced by the interaction of oxidation products of phenol and amine. 

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 health impairing and toxic elfects of oxidation of lipids are due to loss of vitamins, polyenoic fatty acids, and other nutritionally essential components formation of radicals, hydroperoxides, aldehydes, epoxides, dimers, and polymers and participation of the secondary products in initiation of oxidation of proteins and in the Maillard reaction. Dilferent oxysterols have been shown in vitro and in vivo to have atherogenic, mutagenic, carcinogenic, angiotoxic, and cytotoxic properties, as well as the ability to inhibit cholesterol synthesis (Tai et ah, 1999 Wpsowicz, 2002). 

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