Lipid peroxidation initiators

In contrast to numerous literature data, which indicate that protein oxidation, as a rule, precedes lipid peroxidation, Parinandi et al. [66] found that the modification of proteins in rat myocardial membranes exposed to prooxidants (ferrous ion/ascorbate, cupric ion/tert-butyl-hydroperoxide, linoleic acid hydroperoxide, and soybean lipoxygenase) accompanied lipid peroxidation initiated by these prooxidant systems. 

It is noteworthy that Aust and coworkers have shown that in vitro lipid peroxidation initiated by ferrous-ADP or ferrous-AMP complexes was strongly stimulated by the presence of the analogous ferric complexes, with no effect of either SOD, catalase or OH scavengers [156,157]. This suggests that a ferrous-dioxygen-ferric chelate may serve as a potent free radical initiator of its own. 

Cojocel C, Hannemann J, Baumann K. Cephaloridine-induced lipid peroxidation initiated by reactive oxygen species asa possible mechanism of cephaloridine nephrotoxicity. Biochim Biophys Acta 1985 834 402-410. 

It is known that superoxide forms complexes with Ca ", thereby permitting formation of calcium peroxide. Since the majority of biological membranes translocate Ca or other alkali metal ions, the opportunity for interaction with superoxide within the membrane may be considerable (Ca " and calmodulin are required for superoxide production by leukocytes ). Under pathological circumstances calcium peroxide could be formed and lipid peroxidation initiated. The breakdown of membrane capacitance as a consequence of this may be deleterious in a number of ways. For example, the loss of a critical electric field may remove the driving force for energy-dependent processes associated with charge transfer. On the other hand, circumstances may be established which bring about unrestrained and unmodulated metabolic activity, as in cancer. 

Gorelik, S. and Kanner, J. Oxymyoglobin oxidation and membranal lipid peroxidation initiated by iron redox cycle. J. Agric. Food Chem. 49, 5939-5944 (2001). 

Figure 14-21. Lipid peroxidation. The reaction is initiated by an existing free radical (X ), by light, or by metal ions. Malondialdehyde is only formed by fatty acids with three or more double bonds and is used as a measure of lipid peroxidation together with ethane from the terminal two carbons ofcoB fatty acids and pentane from the terminal five carbons of cb6 fatty acids.

However, peroxidation can also occur in extracellular lipid transport proteins, such as low-density lipoprotein (LDL), that are protected from oxidation only by antioxidants present in the lipoprotein itself or the exttacellular environment of the artery wall. It appeats that these antioxidants are not always adequate to protect LDL from oxidation in vivo, and extensive lipid peroxidation can occur in the artery wall and contribute to the pathogenesis of atherosclerosis (Palinski et al., 1989 Ester-bauer et al., 1990, 1993 Yla-Herttuala et al., 1990 Salonen et al., 1992). Once initiation occurs the formation of the peroxyl radical results in a chain reaction, which, in effect, greatly amplifies the severity of the initial oxidative insult. In this situation it is likely that the peroxidation reaction can proceed unchecked resulting in the formation of toxic lipid decomposition products such as aldehydes and the F2 isoprostanes (Esterbauer et al., 1991 Morrow et al., 1990). In support of this hypothesis, cytotoxic aldehydes such as 4-... 

Scheme 2.1 The key reactions that occur during lipid peroxidation, in this scheme, X represents the initiating species, which must be a highiy reactive oxidant, in order to abstract a H atom from a poiyunsaturated fatty-acid chain LH, the iipid substrate LO2, the peroxyi radicai L, the alkyl radical LOOH, the lipid hydroperoxide.

Since the peroxyl and alkyl radicals are regenerated, the cycle of propagation could continue indefinitely or until one or other of the substrates are consumed. However, experimentally the length of the propagation chain, which can be defined as the number of lipid molecules converted to lipid peroxide for each initiation event, is finite. This is largely because the cycle is not 100% efficient with peroxyl radicals being lost through radical-radical termination reactions (Reaction 2.4 in Scheme 2.1). 

It is easier to abstract a hydrogen atom and initiate lipid peroxidation from a fatty acid that has bis-allylic centres than from a fatty-acid side chain with only one double bond. It follows, therefore, that fatty-acid composition should influence the ability of a molecule such as LDL to act as a substrate for peroxidation. The potential... 

Not all oxidants formed biolc cally have the potential to promote lipid peroxidation. The free radicals superoxide and nitric oxide [or endothelium-derived relaxing aor (EDRF)] are known to be formed in ww but are not able to initiate the peroxidation of lipids (Moncada et tU., 1991). The protonated form of the superoxide radical, the hydroperoxy radical, is capable of initiating lipid peroxidation but its low pili of 4.5 effectively precludes a major contribution under most physiological conditions, although this has been suggested (Aikens and Dix, 1991). Interestingly, the reaction product between nitric oxide and superoxide forms the powerful oxidant peroxynitrite (Equation 2.6) at a rate that is essentially difiiision controlled (Beckman eta/., 1990 Huie and Padmaja, 1993). 

In this reaction scheme, the steady-state concentration of peroxyl radicals will be a direa function of the concentration of the transition metal and lipid peroxide content of the LDL particle, and will increase as the reaction proceeds. Scheme 2.2 is a diagrammatic representation of the redox interactions between copper, lipid hydroperoxides and lipid in the presence of a chain-breaking antioxidant. For the sake of clarity, the reaction involving the regeneration of the oxidized form of copper (Reaction 2.9) has been omitted. The first step is the independent decomposition of the Upid hydroperoxide to form the peroxyl radical. This may be terminated by reaction with an antioxidant, AH, but the lipid peroxide formed will contribute to the peroxide pool. It is evident from this scheme that the efficacy of a chain-breaking antioxidant in this scheme will be highly dependent on the initial size of the peroxide pool. In the section describing the copper-dependent oxidation of LDL (Section 2.6.1), the implications of this idea will be pursued further. 

Oxidation of the fatty acids in an LDL particle shares many of the characteristics associated with lipid peroxidation in other biological or chemical systems. Once initiated peroxyl radicals are formed and this results in the oxidation of a-tocopherol to give the a-tocopheroyl radical (Kalyanaraman etal., 1990). This can be demonstrated by e.s.r. techniques that allow the direct observation of stable radicals such as the a-tocopheroyl radical. After the a-tocopheryl radical is consumed, lipid-derived peroxyl radicals can be detected after reaction with spin traps (Kalyanaraman etal., 1990, 1991). 

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