Hydrogen abstraction lipids

Monooxygenases. Under nonlignolytic conditions, arene monooxygenase and epoxide hydrolase systems may function to produce trani-dihydrodiols. Hydrogen abstraction mediated by the lipid peroxidase system may operate, for example, in the formation of fluorene-9-one from fluorene by Ph. chrysosporium (Bogan et al. 1996). 

The H-abstraction reactions of peroxyl radicals are related to ET discussed above, as in both cases the same final product is formed, a hydroperoxide. Mechanistically, these two processes are, of course, different. Hydrogen-abstraction reactions by peroxyl radical, including H02-, are common (cf. the autoxidation of polyunsaturated lipids Hasegawa and Patterson 1978 Patterson and Hasegawa 1978 Patterson 1981 Porter et al. 1981 Gebicki and Bielski 1981 Barclay et al. 1989 Zhu and Sevilla 1990 Aikens and Dix 1991 Simic et al. 1992). This H-abstraction reaction may occur inframolecularly as well as infermolecularly [cf. reactions (29) and (30)]. 

Initiation of lipid peroxidation can proceed by hydrogen abstraction (Pryor and Castle, 1984) or possibly by an addition reaction (Willson, 1979 Porter, 1984). Naturally occurring PUFAs usually contain methylene interrupted structures, e.g., R-CH = CH-CH2-CH = CH-R2. The presence of carbon-carbon double bonds weakens carbon-hydrogen bonds in the adjacent methylene group and facilitates hydrogen atom abstraction thus ... 

The now classic Farmer-type hydrogen-abstraction Initiation of free radical autoxldatlon accounts for a large portion of the nonenzymlc oxidations of n-3 fatty acids (45). Because fish lipids contain substantial concentrations of EPA and DHA (47-48), they provide many allowed sites (18, 22, 45, 46, 49) of hydroperoxide formations, and thus can account for a large array of decomposition products. Oxidizing model systems of unsaturated methyl esters of fatty acids yielded monohydroperoxides, but also produce dlhydroperoxldes that are formed by cycllzatlon of Intermediate hydroperoxy radicals when suitable H-donatlng antioxidants are not present to quench the free radical reaction (45, 50, 51). Decomposition of monohydroperoxides of fatty acids In model systems yields a very different profile of lower molecular weight products than observed for similar decompositions of dlhydroperoxldes of the same fatty acids (45, 46). 

Figure 1. Classic free radical chain reaction mechanism of lipid oxidation with propagation by a series of hydrogen abstractions.

Citation of the classic chain reaction for lipid oxidation persists even though, as product analysis and studies of mechanisms have become more sophisticated, there is now considerable evidence that only Reactions 1, 2, and 5 (and perhaps also 6) of Figure 1 are always present. Research has shown that, although hydrogen abstraction ultimately occurs, it is not always the major fate of the initial peroxyl or alkoxyl radicals. Indeed, lipid alcohols from H abstraction are relatively minor products of lipid oxidation. There are many competing alternative reactions for LOO and LO that propagate the radical chain but lead to different kinetics and different products than expected from the classic reaction sequence (5, 6, 21). A more detailed consideration of each stage shows how this basic radical chain sequence portrays only a small part of the lipid oxidation process and products, and a new overall reaction scheme for lipid oxidation is needed. 

Direct initiation through higher valence metals involves direct electron transfer from the metal to a bond in the lipids and is the simplest mechanism for metal catalysis. Electron transfer to methyl linoleate is exothermic (AH= 62.8kJ, ISkCal), so is probably the dominant initiation mechanism with lipids (23, 27). Ab initio hpid radicals are formed directly by removing an electron from a double bond (Reaction 2) (28, 29) or, more generally, from the C H bond of any labile H in lipid molecules (e.g., allylic hydrogens) (Reaction 3), or via subsequent secondary hydrogen abstraction reactions, as designated in the bracketed reactions. 

The principal light-absorbing groups of lipids are double bonds, peroxide 0—0 bonds, and carbonyls the last two are most important. The primary mechanism by which ultraviolet radiation initiates lipid oxidation is actually indirect, mediated through homolytic scission of any preformed hydroperoxides to generate the true initiators— LO, HO, and RO —that abstract hydrogens from lipid molecules and form the ab initio L. ... 

TABLE 2. Lifetimes and Hydrogen Abstraction Rates of Various Radicals that Initiate Lipid Oxidation. 

Atom Transfer (hydrogen abstraction) by LOO —> Free Radical Chain Reactions Hydrogen abstraction is the heart of the classic free radical chain reaction schemes (Figure 1). Peroxyl radicals initially formed at any site on a fatty acid pass the unpaired electron to adjacent lipid molecules by abstracting hydrogens from an allylic position or a hydroperoxide, and the process repeats itself indefinitely until the chain is intercepted. 

This presents an interesting analytical quandary. Epoxides are major products of lipid oxidation and derive from LO cyclization as well as LOO additions (see Section 3.2.2). Consequently, it may be difficult to determine the mechanism that is operative in a given reaction system, and indeed, both may contribute. For example, Hendry (283) reacted a series of ROO with their parent compounds at 60°C and found 40% of the products were epoxides. Rate constants of k = 20 to 1130 M sec were calculated assuming the reactions were aU additions, but at the elevated temperature of the study, hydrogen abstraction to form the hydroperoxides, followed by homolytic scission to alkoxyl radicals, could also have contributed to the yields. 

Hydrogen Abstraction by LC3 LO abstractions are very fast (k lO -10 L M s ), but less selective than LOO (198) they abstract both aUylic and bis-allylic hydrogens, whereas LOO abstracts only the latter (261). AUylic hydrogens are particularly susceptible to abstraction by sec alkoxyl radicals (21), so the H abstractions by lipid alkoxyl radicals, as written in the classic free radical chain (Reaction 52), should be a preferred reaction in lipid oxidation ... 

Hydrogen abstraction by LO to propagate free radical chains is facile also in nonpolar aprotic solvents when lipids are at high concentrations. However, at moderate lipid concentrations, H abstraction must compete with internal rearrangements and scission (304), and at low concentrations it may become insignificant (305). 

Therefore, a new integrated paradigm for lipid oxidation is proposed in which the major alternative pathways are added to the classic free radical chain (Figure 15). The traditional reaction sequence involving hydrogen abstractions is presented vertically down the center of the scheme because most radicals formed in alternative reactions ultimately abstract hydrogens to propagate the chain. This is the core of the oxidation process. Pathways that compete with H abstraction are... 

Figure 15. Integrated scheme for lipid oxidation accounting for multiple reactions pathways competing with the classic hydrogen abstraction. Dotted lines indicate paths for oxygen addition to secondary radicals formed in cyclic and addition products, with formation of new peroxyl radicals.

Lipid peroxidation can be divided into three separate processes - initiation, propagation, and termination. During initiation a very small number of radicals (e.g., transition metal ions or a radical generated by photolysis or high-energy irradiation) can abstract hydrogen from lipid molecules to yield free radicals of lipids... 

Fig. 4. Mechanism of lipid peroxidation and its inhibition by vitamin E. Lipid peroxidation is initiated by generating a relatively nnreactive carbon-centered radical upon hydrogen abstraction by a hydroxyl radical (1). The fast formation (2) of the more reactive peroxyl radicals (ROO) ensures rapid attack of any peroxidizable substrate either by abstraction of a hydrogen atom (3a) or addition to a double bond (3b). The propagation is teiminated by mutual elimination of peroxyl radicals (4) or by suppression of free-radical formation in the presence of a-tocopherol (a-TOH) (5a). The tocopheryl radical is believed to be neutralized by ascorbic acid (AscAH) (5b) and radical oxygen, and a-tocopherol then re-enters the inhibition cycle.

In biological systems, free radicals can react with cellular macromolecules in a variety of ways, the most important of which is hydrogen abstraction from DNA leading to chain scission or cross-linking. In proteins, tryptophan is the amino acid residue most susceptible to free radical attack. Lipid peroxidation by free radicals in turn is liable to cause alteration in cell membranes. 

Hydrogen abstraction from lipids by triplet states of benzophenone derivatives followed directly by the use of laser flash techniques allows the separation of physical quenching processes from chemical reactions of the excited state. 98 xhe production of 2 by the photochemical decomposition of aromatic endoperoxides has also been studied by ps kinetic procedures. 99 mechanistic study has also been reported on the phototransformation of 3-nitrophenol in aqueous solution. 99 There is a strong wavelength dependence of the low quantum yield for the phototransformation in this system. 

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