Lipid radicals

Ogura, R, Sugiyama, M., Nishi, J. and Haramaki, N. (1991). Mechanism of lipid radical formation following exposure of epidermal homogenate to ultraviolet light. J. Invest. Dermatol. 97, 1044-1047. 

Figure 17.2 Lipid peroxidation scheme. LH, a polyunsaturated fatty acid LOOM, lipid hydroperoxide LOH, lipid alcohol L, lipid radical LOO, lipid hydroperoxyl radical LO, lipid alkoxyl radical. Initiation the LH hydrogen is abstracted by reactive oxygen (e.g. lipid alkyl radical, lipid alkoxy radical, lipid hydroperoxyl radical, hydroxy radical, etc.) to produce a new lipid alkyl radical, L. Propagation the lipid alkyl, alkoxyl or hydroperoxyl radical abstracts hydrogen from the neighbouring LH to generate a new L radical.

Figure 7. Relationship of oxidation and degree of polyunsaturation. Polyunsaturation is measured as the methylene bridge index (MBI), which is a more precise measure of extent of unsaturation and oxidizability than the double bond index. It is the mean number of 6is-allylic methylene bridge positions per fatty acid (or fatty acyl chain) in a lipid ensemble. The rate of lipid radical formation measures formation of an oxidative product, while O2 consumption (% O2 lost per sec) is a measure of utilization of a reactant. (Drawn using our data abstracted from Wagner, B.A., Buettner, G.R., and Bums, C.P. 1994, Biochemistry 33 4449-4453).

Oxidation to CO of biodiesel results in the formation of hydroperoxides. The formation of a hydroperoxide follows a well-known peroxidation chain mechanism. Oxidative lipid modifications occur through lipid peroxidation mechanisms in which free radicals and reactive oxygen species abstract a methylene hydrogen atom from polyunsaturated fatty acids, producing a carbon-centered lipid radical. Spontaneous rearrangement of the 1,4-pentadiene yields a conjugated diene, which reacts with molecular oxygen to form a lipid peroxyl radical. 

Dose and duration dependence of free radical generation during carbon tetrachloride metabolism in the endoplasmic reticulum relation between trichloromethyl radical formation and lipid radical format on. 

As exemplified in Figure 2, Type 1 mechanism, electron transfer from L to sens yields two radicals, the substrate radical, L", and the sensitizer radical anion (sens ). In the next step, the lipid radical may induce a chain peroxidation cascade involving propagation reactions -The sensitizer radical anion may also start a sequential one-electron reduction of 2 generating HO in the presence of reduced transition metals. As a result, this may lead to abstraction of a lipid allylic hydrogen with subsequent generation of a carbon-centered lipid radical, L, that is rapidly oxidized to a peroxyl radical (vide supra). 

Cyt c is associated with the outer surface of the inner mitochondrial membrane. Phospholipids induce conformational changes in the protein and, in certain instances, the haem can convert to the high spin (S = 5/2) form, indicative of a weakening of the ligand field caused by displacement of the sixth ligand (Met-80). This has been associated with the detection of lipid radicals by direct EPR (at 11 K).65 Indeed, peroxidase-type activity is also evident in the reaction of cyt c with lipid hydroperoxides, as studied by spin trapping in conjunction with HPLC and MS.66... 

Akaike et al. have examined the neuroprotective properties of serofendic acid, a substance isolated from serum. The compound was found to protect neuronal cells from both glutamate and NO. This was attributed to the scavenging of OH radicals (from the decomposition of ONOO-) rather than NO itself.320 Indeed, Ueda and colleagues have demonstrated the formation of both NO and OH in neuronal cells upon stimulation of the NMDA receptor.321 These workers also trapped lipid radicals in the brains of rats undergoing seizures induced by the stimulation of a subset of glutamate receptors with kainic acid. Polyphenols have been shown to exacerbate the neurotoxicity of NO.322... 

Numerous studies have indicated that pro-inflammatory mediators (cytokines) are involved in the destruction of the insulin-producing p-cells of the pancreas in the development of type I diabetes. Tabatabaie et al. introduced cytokines and PBN into the pancreas of rats. The analysis of pancreatic extracts revealed that the cytokines stimulate the formation of lipid radicals. Radical generation did not occur in rats treated with streptozotocin, which destroys the P-cells.33 Evidence for the role of radicals in diabetes has also been provided by spin trapping studies in pancreatic homogenates, showing that streptozotocin, which is often used to induce the condition in laboratory animals, stimulates OH production.332 Other workers, using EPR to observe the decay of a spin probe in the abdomen of mice (at 1.2 GHz), have demonstrated that strep-... 

This cascade however may be propagated throughout the cell unless terminated by a protective mechanism (see below) or a chemical reaction such as disproportionation, which gives rise to a non-radical product. Polyunsaturated fatty acids, found particularly in membranes, are especially susceptible to free radical attack. The effects of lipid peroxidation are many and various. Clearly, the structural integrity of membrane lipids will be adversely affected. In the lipid radical produced, the sites of unsaturation may change, thereby altering the fluidity of the membrane (see chap. 3). Lipid radicals may interact with other lipids and... 

Lipid radicals and other radicals may be removed by a number of endogenous compounds as well as GSH. One is vitamin E, (which includes a-tocopherol) a lipophilic substance. It can react with and neutralize lipid radicals and hydroperoxides, in the process becoming a free radical itself. This a-tocopheryl radical is relatively stable and can then be converted back into the a-tocopherol by vitamin C (ascorbate) or react with more radicals and become a-tocopherol quinone ... 

The resulting lipid peroxides, if not detoxified, may give rise to lipid radicals and membrane damage. However, although there is experimental evidence that paraquat causes lipid peroxidation, there is little direct evidence from in vivo studies. This may reflect the fact that only a small proportion of lung cells are affected. 

The inhibition of lipid (LH) oxidation may be considered as one of the most important chemical reaction mechanisms that could explain the antioxidant function of flavonoids. In general terms, chain-breaking antioxidants (AH) inhibit or retard lipid oxidation (reactions 1-7) by interfering with initiation [generically represented by reaction 1] or with chain propagating reactions (reactions 2 and 3) by readily donating hydrogen atoms to lipid peroxyl radicals (LOO ) or lipid radicals (L ) (reactions 4 and 5) [Frankel, 1998] ... 

Since DNA is a highly charged polyanion, it is always hydrated by water molecules [in the dry state (under moist air) it contains 12 water molecules per nucleotide subunit]. In a cellular environment, proteins (histones in eukaryotic cells) are always attached to DNA or are at least surrounded by proteins as in viruses. In order to attack DNA, radicals have to be sufficiently mobile in such a partially hydrophilic environment. For this reason, typical lipid radicals confined to the membranes will not be discussed here, although one must keep in mind that small fragments of free-radical nature maybe able to escape the lipid environment and can, in principle, also react with DNA. 

Fig. 7.3 Reactions showing the generation of ROS during lipid peroxidation and oxidative stress. Hydroxyl radical ( OH) lipid radical ( lipid), peroxyl radical (lipid-OO ) lipid peroxide (lipid-OOH) nitric oxide ( NO) nitrogen dioxide (N02) peroxynitrite anion (ONOO-) hypochlorous acid (HOC1), and hydrogen peroxide (H202)...

Reaction of the lipid radical with molecular oxygen yields peroxy radical species ... 

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