Chain Reaction Of Lipid Peroxidation Research Articles

Impairment of acetylcholine relaxations by malondialdehyde, a marker of lipid peroxidation.

The effect of malondialdehyde (MDA), a lipid peroxidation marker, on the relaxations evoked by acetylcholine (ACh) was analyzed in tail arteries of Sprague-Dawley rats, which have MDA plasma levels of 0.43 +/- 0.10 microM. MDA (0.5-30 microM) produced an inhibition of ACh relaxations that persisted after repeated washing periods, and was independent of the incubation time. MDA did not modify the vasodilator responses to either exogenous nitric oxide (NO) or sodium nitroprusside, a NO donor. L-Arginine (the NO synthase substrate) did not prevent the impairment of relaxations to ACh caused by MDA. The association of N omega-nitro-L-arginine methyl ester (a NO synthase inhibitor) and MDA produced an additive inhibition of the ACh-induced relaxations. Superoxide dismutase (a superoxide anion scavenger) completely reversed the inhibitory effect of MDA. These results suggest: (1) MDA is not only a marker of lipid peroxidation but also an agent that can impair endothelium-dependent relaxations; (2) this impairment does not seem to be due to an interference with guanylate cyclase activation by NO or with NO synthase pathway; (3) the effect of MDA appears to be mediated by superoxide anion, and (4) MDA could propagate lipid peroxidation chain reactions in endothelial membranes, that could alter the function of muscarinic receptors.

Anti-oxidant actions of oxymethazoline and xylomethazoline

Anti-oxidant actions of oxymethazoline and xylomethazoline were investigated by measuring inhibition io microsomal lipid peroxidation and hydroxyl radical scavenging activity. Oxymethazoline was shown to be potent inhibitir of lipid peroxidation (IC 50 = 4.9 μM at t = 15 min, IC 50 = 81. μM at t = 30 min), in contrast to xylomethazoline. Both compounds were excellent hydroxyl radical scavengers. Their rate constants ( k S = 1.1 × 10 12 M −1s −1 for oxymethozoline and k S = 4.7 × 10 10 M −1s −1 for xylomethazoline) exceeded the rate constant of a known powerful scavenger cimetidine ( k S = 1.8 × 10 10 M −1S −1). The difference in inhibiting lipid peroxidation might be explained by the fact that only oxymethazoline has a hydroxy group which can donate a hydrogen atom and terminate the chain reaction of lipid peroxidation. The mechanism of hydroxyl radical scavenging activity is still unclear. Moreover oxymethazoline seems to have a different mode of action in scavenging hydroxyl radicals than oxylomethazoline and cimetidine which results in an extremely high rate constant. Because oxidants play a role in tissue damage in inflammation, it was hypothesized that especially oxymethazoline and to a lesser extent xylomethazoline may have an additional beneficial effect, due to their anti-oxidant properties, in the topical treatment of nasal inflammation.

Kinetic study of quenching reaction of singlet oxygen and scavenging reaction of free radical by squalene in n-butanol

The rate constant of quenching of singlet oxygen ( k Q ) by squalene (SO) is found to be much larger than those of the lipids in human skin surface. SQ is the first target lipid in human skin surface by oxidative stresses such as sun light exposure. k Q of SQ is similar to that of 3,5-di- t-butyl-4-hydroxytoluene (BHT). The large k Q of SQ is due to the small ionization potential. SQ consists of six 2-methyl-2-pentene units and k Q of SQ is about 6-times as large as that of 2-methyl-2-pentene. The electron donating property of methyl groups bonded to quaternary carbons of SQ is essential to the large k Q . SQ is not very susceptible to peroxidation and is stable for attacks by peroxide radicals. The chain reaction of lipid peroxidation is unlikely to be propagated with SQ in human skin surface. It is concluded that SQ functions as an efficient quencher of singlet oxygen and prevents the corresponding part of lipid peroxidation in human skin surface.

Oxidative stress from environmental pollutants

Recently progress has been made on O2 toxicity and pathology related to numerous environmental contaminants in insects. The pro-oxidants studied included: dioxin, paraquat, and an assorted array of quinones, 8-methoxypsorlen, arsenic, and mercury. The responses to these oxidants are diverse, but they arise from the reactive oxygen species. These pro-oxidants in insects cause lipid peroxidation, protein and enzyme oxidation, and GSH depletion. Potentially, they may also cause DNA oxidation, and form DNA adducts. Oxidative challenge is alleviated by antioxidant compounds, but more importantly by the induction of antioxidant enzymes, which are crucial for the termination of O2 radical cascade and lipid peroxidation chain reaction. Insects exhibit a wasting syndrome under sub-acute stress. In acute toxicity vital physiological processes impaired are hemolymph melanization and diuresis. Thus, insects resemble vertebrates in both the response to oxidative stress and its pathological consequences. These results raise the prospect that insects may serve as non-mammalian model species for monitoring the oxidative-stress component of environmental toxicity.

Polymorphonuclear leukocytes-induced injury in hypoxic cardiac myocytes

Growing evidence suggests that free radicals derived from polymorphonuclear leukocytes (PMNs) play an important role in myocardial ischemia-reperfusion injury. To elucidate the cellular mechanism by which activated PMNs exacerbate ischemic myocardial damage, we investigated the extent of cell injury, assessed by the morphological deterioration, free radical generation, and lipid peroxidation in mouse embryo myocardial cells coincubated with activated PMNs. The generation of PMN-derived free radicals was related to the extent of myocardial cell injury. When myocardial cell sheets were subjected to hypoxia and glucose-free media, myocardial cells were injured (cristalysis in the mitochondria and disruption of the sarcolemma) after adding various PMN activators, and the injury extended to the adjacent cells. Chemiluminescent emission and production of thiobarbituric acid-reactive substances in the coincubated cells increased markedly compared with myocardial cells or PMNs alone. The augmented lipid peroxidation coincided with the progression of myocardial cell injury. Catalase inhibited the myocardial cell injury by 52%, the chemiluminescence by 46%, and lipid peroxidation by 50%, whereas superoxide dismutase exhibited less pronounced inhibition. These results indicate that a chain reaction of lipid peroxidation in myocardial cells induced by PMN-derived free radicals closely correlates with membrane damage and contributes to the propagation of irreversible myocardial cell damage.

Antioxidants reduce peroxyl-mediated inhibition of mitochondrial transcription

We have recently shown that the mitochondrial transcription system is extremely sensitive to inhibition by peroxyl radicals generated by either 2,2′-azobis(2-amidinopropane) (AAPH) or 2,2′-azobis(2,4-dimethylvaleronitrile) (AMVN), and that this inhibition occurs prior to detectable evidence of lipid peroxidation as measured by thiobarbituric acid (TBA)-reactive substances, 4-hydroxynonenal accumulation, and oxygen consumption. In this report, we further confirm that mitochondrial transcription is sensitive to oxidative stress. We also demonstrate that α-tocopherol, ascorbate and glutathione can partially attenuate these effects, but none of the three, nor the three together, are capable of completely preventing this oxidant-induced repression. This suggests that these physiological antioxidants, while capable of preventing lipid peroxidation chain reactions, are less effective at protecting the mitochondrial transcriptional machinery against this oxidative insult.

The oxidant stress hypothesis in Parkinson's disease: Evidence supporting it

Oxidant stress, due to the formation of hydrogen peroxide and oxygen-derived free radicals, can cause cell damage due to chain reactions of membrane lipid peroxidation. Because the substantia nigra is rich in dopamine, which can undergo both enzymatic oxidation via monoamine oxidase and nonenzymatic autoxidation, hydrogen peroxide and oxyradicals (superoxide anion radical and hydroxyl radical) are generated in this midbrain nucleus. Although proof that oxidant stress actually causes the loss of monoaminergic neurons in patients with Parkinson's disease is lacking, there is a considerable body of evidence from studies in both animals and humans that support the concept. (1) Neurotoxins that selectively destroy the dopaminergic neurons in the nigra, such as 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), appear to act via oxidant stress. (2) The substantia nigra of patients with Parkinson's disease reveals evidence of oxidant stress by the findings of increased lipid peroxidation and decreased reduced glutathione. (3) Total iron is increased and ferritin is reduced in the substantia nigra pars compacta in patients with Parkinson's disease. This combination suggests that this transition metal is in a low molecular weight form, capable of catalyzing nonenzymatic oxidative reactions, especially the conversion of hydrogen peroxide to hydroxyl radical, which is the most reactive of the oxygen radicals. (4) Neuromelanin, a product of dopamine autoxidation, can serve as a reservoir for iron, promoting the generation of oxyradicals. (5) Antioxidant defense mechanisms appear to be reduced in the parkinsonian substantia nigra with the findings of decreased activities of glutathione peroxidase and catalase.(ABSTRACT TRUNCATED AT 250 WORDS)

Biochemical defence of pro-oxidant plant allelochemicals by herbivorous insects

A new aspect of interactions among insect herbivores and defensive chemistry of plants in the regulation of oxygen toxicity exerted by pro-oxidant allelochemicals is described. Endogenous oxygen toxicity results from activation of the ground state of molecular oxygen to the superoxide anion radical (O 2· −), hydrogen peroxide (H 2O 2), hydroxyl radical (·OH), lipid hydroperoxides (LOOHs), and peroxyl radicals (LO 2· or RO 2·). The strongly lipid-peroxidizing singlet oxygen ( 1Δg O 2 ) is also produced during light activation of photosensitizers. Ingestion of pro-oxidants exacerbates oxygen toxicity by increasing the production of these deleterious forms of oxygen. The role of ascorbate, α-tocopherol, glutathione, carotenoids and urate as antioxidants in insects is apparent, but needs more work for the elucidation of their roles. The major defence mechanism includes a group of antioxidant enzymes represented by superoxide dismutase (SOD), catalase (CAT), glutathione-S- transferase's peroxidative activity (GSTPX), glutathione reductase (GR), and DT-diaphorase, SOD converts O 2· − radicals to H 2O 2 and O 2, CAT decomposes H 2O 2 to H 2O and O 2, GSTPX reduces LOOHs to LOHs with GSH as reductant, and GSSG formed from GSH during the GSTPX reaction is reduced to GSH by GR. DT-diaphorase is an important antioxidant in that it reduces quinones by a two-electron reduction to stable products, thereby preventing the one-electron reduction to semiquinone radicals which generate O 2· − radicals. Therefore, these enzymes are crucial for insect herbivores for preventing the free-radical cascade of oxygen, and terminating the toxic lipid peroxidation chain reaction, in response to the endogenous and potential exogenous oxidant-induced injury.

A promising approach for improving the recovery of heart transplants: Prevention of free radical injury through iron chelation by deferoxamine

Iron catalysis is involved in the generation of the highly cytotoxic hydroxyl radical and in the chain reactions of subsequent lipid peroxidation that lead to irreversible membrane damage. Assuming that ischemically stored heart transplants may incur free radical injury at the time of reoxygenation, we assessed the effects of the iron chelator deferoxamine in 70 isolated isovolumic buffer-perfused rat hearts subjected to the following protocol: cardioplegic arrest; cold (2 degrees C) storage for 5 hours; global ischemia at 15 degrees C for 1 hour, intended to simulate the implantation procedure; and normothermic reperfusion for 1 additional hour. During poststorage ischemic arrest, the following techniques of myocardial protection were evaluated: hypothermia alone; high-pressure (60 cm H2O) cardioplegia given at 0, 30, and 55 minutes of arrest; low-pressure (30 cm H2O) cardioplegia given at 0 and 55 minutes of arrest; and low-pressure (30 cm H2O) cardioplegia only given at 55 minutes of arrest. Treated hearts had deferoxamine (6 mumol) added to the cardioplegic solution used throughout the experimental time course. Further, in the treated group subjected to the protocol of single cardioplegic delivery at end ischemia, deferoxamine was given both in the cardioplegic reperfusate and in the Krebs buffer over the 15 initial minutes of reflow. Based on comparisons of postreperfusion ventricular pressure development, maximal rate of rise of ventricular pressure, left ventricular compliance, and coronary flow, the best myocardial protection was afforded by deferoxamine given as an additive to single-dose cardioplegic solution at the end of arrest and to the reperfusate during the initial phase of reoxygenation. As the drug has no inotropic effect, its protective action is most likely related to a decrease in catalytic iron available for free radical production and lipid peroxidation. These results support the hypothesis that oxidative damage may contribute to donor heart failure and demonstrate that this form of damage can be efficiently acted upon by iron chelation. The clinical relevance of these data stems from the fact that deferoxamine is available for human use and might become an effective means of improving donor heart preservation in the setting of clinical heart transplantation.

Superoxide dismutase amplifies dye photosensitized production of desferal free radical: An electron spin resonance study

Desferal free radical (DFFR) photogenerated from dye sensitization was studied by electron spin resonance. When irradiated at the visible maximum in the presence of O2, both rose bengal and riboflavin sensitized the oxidation of Desferal (DF) and generated the DFFR. The yield of DFFR was amplified by superoxide dismutase (SOD). The SOD enhancement was attributed to the inhibition of superoxide-induced DFFR destruction. Similar SOD enhancement was observed with dyes Rhodamine 123 and Gentian Violet. Our studies suggest that when Desferal is used as a chelating agent in the presence of SOD, systems involving O2- could face interference from DFFR even at concentrations as low as 10 microM DF. DFFR may interfere with the chain reaction of lipid peroxidation resulting in an apparent protective action which, in fact, has very little to do with chelating the catalytic iron.

Effects of arachidonic acid and inhibitors of arachidonic acid metabolism on phagocyte-induced sister chromatid exchanges.

Stimulated human phagocytes produce toxic oxygen radicals which induce sister chromatid exchanges in cultured mammalian cells. Oxidative damage to membranes initiates lipid peroxidation chain reactions and stimulation of the arachidonic acid cascade. The products of these reactions may mediate the genetic toxicity of oxygen radicals. Arachidonic acid significantly augmented the number of sister chromatid exchanges in target cells exposed to stimulated phagocytes. This genetic damage was abrogated in radical-treated cells preincubated with inhibitors of the cyclooxygenase (indomethacin), lipoxygenase (nordihydroguaiaretic acid) or both (piroxicam) pathways.

Effects of inhibitors of arachidonic acid metabolism and vitamin E on oxygen radical-induced sister chromatid exchanges.

Oxidative damage to membranes initiates lipid peroxidation chain reactions and stimulation of the arachidonic acid cascade. The products of these reactions may mediate the genetic toxicity of oxygen radicals. Arachidonic acid alone induced sister chromatid exchange (SCE) formation and significantly augmented the genetic damage observed with an oxygen radical-generating system. The number of SCEs was reduced significantly in oxygen radical-treated Chinese hamster ovary cells incubated with inhibitors of the cyclo-oxygenase and lipoxygenase pathways. Vitamin E, when combined with inhibitors of arachidonic acid metabolism, protected target cells completely from oxygen radical-induced genotoxicity. These data support the hypothesis that lipid peroxidation intermediates may be involved in the genesis of radical-generated genetic lesions.

Formation of monohydroxy-polyenic fatty acids from lipid peroxides by a glutathione peroxidase

1. 1. It has been confirmed that the oxidation of GSH by linoleic acid hydroperoxide is enzymically catalyzed in rat liver. 2. 2. By thin-layer chromatography, gas-liquid chromatography and mass spectrometry, and by chemical modifications such as acetylation, methylation and hydrogenation, the products formed by the enzymic removal of linoleic acid hydroperoxide have been identified as 9-hydroxy-10,12-octadecadienoic acid and 13-hydroxy-9,11-octadecadienoic acid. The hydroperoxide can thus be detoxified to products that can be metabolized in the cell. 3. 3. It is suggested that the extremely rapid enzymic reaction of GSH with lipid hydroperoxides breaks the autocatalytic chain reactions of lipid peroxidation and thus protects the vital cellular compounds from the effect of lipid peroxides.