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PubMed1980

Lipid peroxidation in guinea pig lung microsomes.

The effects of substances known to influence lipid peroxidation were studied in guinea pig lung microsomes by measuring the formation of malonaldehyde in vitro. Incubation of lung microsomes at 37 degrees C results in lipid peroxidation which appears to be an enzymatic process but is not dependent upon iron. Lipid peroxidation can be initiated non-enzymatically in lung microsomes by Fe2+, but ascorbate and Fe3+ have very little effect on malonaldehyde formation. The effects of NADPH on lipid peroxidation are dependent upon the concentration of Fe2+ in the incubation medium. At concentrations of Fe2+ between 0.05 mM and 1 mM, addition of NADPH causes an increase in lipid peroxidation over that produced by Fe2+ alone. This stimulation by NADPH is an enzymatic process and phosphate is required for the maximal effect. Addition of NADPH to lung microsomes in the presence of Fe3+ does not increase malonaldehyde formation over that produced by Fe3+ alone, suggesting that NADPH does not influence lipid peroxidation by maintaining iron in the reduced form. At concentrations of Fe2+ greater than 1 mM, NADPH inhibits Fe2+-induced lipid peroxidation in normal microsomes and in microsomes in which enzymes have been inactivated with heat. This latter result suggests that the inhibition by NADPH is at least partially non-enzymatic. The result suggests that the inhibition by NADPH is at least partially non-enzymatic. The results of all of these experiments are discussed and compared with those obtained during lipid peroxidation in liver microsomes. We conclude that the processes involved in pulmonary microsomal lipid peroxidation differ significantly from those in hepatic microsomes.

Animals↗

PubMed1992

Cobaltous ion inhibition of lipid peroxidation in biological membranes.

The effect of cobalt on lipid peroxidation in biological membranes, phospholipid liposomes and fatty acid micelles was investigated. Cobaltous ion, at micromolar concentrations, inhibited iron-ascorbate induced lipid peroxidation in erythrocyte ghosts, microsomes and phosphatidylserine liposomes at pH 7.4. The pH seemed to be important for the anti-peroxidative effect of cobalt, because under slightly acidic conditions cobalt did not inhibit peroxidation. Cobalt was less effective in inhibiting peroxidation stimulated by organic hydroperoxides. Iron-ascorbate induced lipid peroxidation was also inhibited by EDTA. However, certain ratios of EDTA: cobalt in the reaction mixture stimulated peroxidation. Cobalt did not inhibit lipid peroxidation in linoleic acid micelles and phosphatidylethanolamine liposomes. The presence of phosphatidylserine, however, rendered these micelles and liposomes to cobalt inhibition. We conclude that the cobaltous ion is a potent inhibitor of lipid peroxidation in biological membranes and that the binding of cobalt to phosphatidylserine is necessary for the inhibitory effect of this metal ion.

Animals↗

PubMed1992

Peroxidation and phospholipase A2 hydrolytic susceptibility of liposomes consisting of mixed species of phosphatidylcholine and phosphatidylethanolamine.

The relationship between lipid peroxidation and phospholipase A2 (PLA2) hydrolytic activity was studied using unilamellar vesicles (liposomes) as model membranes. Hydrolytic specificity was examined using vesicles prepared with pure bovine heart phosphatidylcholine (PC), bovine heart phosphatidylethanolamine (PE), or mixtures of these phospholipids, using two preparative procedures, i.e., sonication or extrusion. Lipid peroxidation was induced by incubating vesicles with cumene hydroperoxide and hematin at 37 degrees C. Determinations of the extent of peroxidation by means of diene conjugate content derived from second derivative spectra or by polarographic measurement of oxygen consumption rates provided a basis for comparing the extent of peroxidation of each phospholipid species to their subsequent hydrolysis by PLA2 (from Crotalus adamanteus). The extent of hydrolysis was determined through the release of arachidonic acid from either PC or PE. The PE distribution among the outer vs. inner leaflet of the membrane bilayer was nearly equal in sonicated vesicles, whereas most of the phospholipid was incorporated into the inner leaflet in extruded vesicles. The proportion of PE found in the inner leaflet progressively increased as the ratio of PE to PC increased in both sonicated and extruded vesicle preparations. Lipid peroxidation had no effect on PE distribution under the conditions examined. There was a clear preference for PC peroxidation for all vesicle compositions tested and PC was preferentially hydrolyzed by PLA2. This effect is proposed to result from a perturbation of membrane structure following peroxidation with assimilation of PC into PLA2-susceptible domains whereas PE peroxidation and hydrolysis is less affected in mixed PC/PE vesicles. Lipid peroxidation imposes an additional hydrolytic susceptibility over the effects exerted through the mixing of these phospholipids which is based on structural changes rather than formation of specific substrates for PLA2.

Animals↗

PubMed1983

The effect of diethyldithiocarbamate on the lipid peroxidation of rat-liver microsomes and intact hepatocytes.

The role of the oxygen radicals in lipid peroxidation, induced by ADP/Fe3+ or cumene hydroperoxide was investigated by administering diethyldithiocarbamate, an inhibitor of superoxide dismutase, to hepatocytes or rats. Intact rat-liver hepatocytes perform a delayed ADP/Fe3+-induced lipid peroxidation after pretreatment with diethyldithiocarbamate. The cumene hydroperoxide-induced lipid peroxidation is unchanged. Hepatocytes, isolated from a rat administered with diethyldithiocarbamate in vivo, exhibit the same pattern, a delayed iron-induced lipid peroxidation and an unchanged cumene hydroperoxide-induced lipid peroxidation. Liver microsomes isolated from liver of a rat administered with diethyldithiocarbamate do not perform lipid peroxidation with NADPH/ADP/Fe3+, but do undergo lipid peroxidation with cumene hydroperoxide. It can be concluded that besides the inhibition of superoxide dismutase, diethyldithiocarbamate inhibits directly the microsomal lipid peroxidation. Although this inhibition hampers the conclusion, evidence is obtained that superoxide dismutase is probably involved in the protection against lipid peroxidation of the mitochondria, but not of the microsomes.

Adenosine Diphosphate↗

PubMed1986

A possible role for membrane lipid peroxidation in anthracycline nephrotoxicity.

Adriamycin causes both glomerular and tubular lesions in kidney, which can be severe enough to progress to irreversible renal failure. This drug-caused nephrotoxicity may result from the metabolic reductive activation of Adriamycin to a semiquinone free radical intermediate by oxidoreductive enzymes such as NADPH-cytochrome P-450 reductase and NADH-dehydrogenase. The drug semiquinone, in turn, autoxidizes and efficiently generates highly reactive and toxic oxyradicals. We report here that the reductive activation of Adriamycin markedly enhanced both NADPH- and NADH-dependent kidney microsomal membrane lipid peroxidation, measured as malonaldehyde by the thiobarbituric acid method. Adriamycin-enhanced kidney microsomal lipid peroxidation was diminished by the inclusion of the oxyradical scavengers, superoxide dismutase and 1,3-dimethylurea, and by the chelating agents, EDTA and diethylenetriamine-pentaacetic acid (DETPAC), implicating an obligatory role for reactive oxygen species and metal ions in the peroxidation mechanism. Furthermore, the inclusion of exogenous ferric and ferrous iron salts more than doubled Adriamycin-stimulated peroxidation. Lipid peroxidation was prevented by the sulfhydryl-reacting agent, p-chloromercuribenzenesulfonic acid, by omitting NAD(P)H, or by heat-inactivating the kidney microsomes, indicating the requirement for active pyridine-nucleotide linked enzymes. Several analogs of Adriamycin as well as mitomycin C, drugs which are capable of oxidation-reduction cycling, greatly increased NADPH-dependent kidney microsomal peroxidation. Carminomycin and 4-demethoxydaunorubicin were noteworthy in this respect because they were three to four times as potent as Adriamycin. In isolated kidney mitochondria, Adriamycin promoted a 12-fold increase in NADH-supported (NADH-dehydrogenase-dependent) peroxidation. These observations clearly indicate that anthracyclines enhance oxyradical-mediated membrane lipid peroxidation in vitro, and suggest that peroxidation-caused damage to kidney endoplasmic reticulum and mitochondrial membranes in vivo could contribute to the development of anthracycline-caused nephrotoxicity.

Animals↗

PubMed1988

Novel membrane localized iron chelators as inhibitors of iron-dependent lipid peroxidation.

Attachment of various iron chelating moieties to hydrophobic steroids greatly enhanced their abilities to inhibit iron-dependent lipid peroxidation. Using whole rat brain homogenates, lipid peroxidation initiated by the addition of 200 microM Fe2+ was assessed by the formation of thiobarbituric acid reactive products (TBAR). Under these conditions, 50% inhibitory concentrations of Fe3+ chelators such as desferrioxamine or N1,N8-bis(2,3-dihydroxybenzoyl) spermidine hydrobromide (compound II) were around 170 and 50 microM respectively. Coupling desferrioxamine or compound II to a steroid at the D ring increased their potency in lipid peroxidation assays by 5- to 10-fold. Evidence that inhibition of lipid peroxidation by the steroid-chelator adducts was due to iron chelation was suggested by the fact that methylation of the catechol oxygens of compound II, which are essential for chelation, completely eliminated activity of the steroid adduct. A series of 21-aminosteroids which complex Fe2+ iron and potently inhibit iron-dependent lipid peroxidation has also been synthesized. Coupling Fe2+ chelators to hydrophobic steroids increased their inhibitory potencies by as much as 10- to 100-fold. Some steroid-based Fe2+ chelators stimulated lipid peroxidation at low concentrations in the presence of Fe3+. The degree of stimulation was related to the affinity of a compound for Fe2+ with the stronger chelators causing greater stimulation. The most potent inhibitors of lipid peroxidation in the 21-aminosteroid series were found to be those compounds forming the weakest Fe2+ complexes. The findings suggest that it is iron at or near the membrane that is responsible for the catalysis of lipid peroxidation. The compounds described should provide useful tools for studies of the involvement of iron in the lipid peroxidation process.

Animals↗

PubMed1993

Evidence that rat liver microsomal glutathione transferase is responsible for glutathione-dependent protection against lipid peroxidation.

Evidence that rat liver microsomal glutathione transferase is responsible for the glutathione-dependent inhibition of lipid peroxidation in liver microsomes has been obtained. Activation of the microsomal glutathione transferase in microsomes by cystamine renders this organelle even more resistant to lipid peroxidation in the presence of glutathione compared with untreated microsomes. Upon examining the effect of seven glutathione analogues on lipid peroxidation, it was found that only those that serve as good substrates for the microsomal glutathione transferase (Glutaryl-L-Cys-Gly and alpha-L-Glu-L-Cys-Gly) can inhibit lipid peroxidation. The lack of inhibition by the other five analogues (alpha-D-Glu-L-Cys-Gly, gamma-D-Glu-L-Cys-Gly, beta-L-Asp-L-Cys-Gly, alpha-L-Asp-L-Cys-Gly and alpha-D-Asp-L-Cys-Gly) shows the specificity of the protection and rules out any non-enzymic component. Inhibitors of selenium-dependent glutathione peroxidase (mercaptosuccinate at 50 microM) and phospholipid hydroperoxide glutathione peroxidase (iodoacetate, 1 mM + glutathione, 0.5 mM) do not inhibit the glutathione-dependent protection of rat liver microsomes against lipid peroxidation. Purified microsomal glutathione transferase, NADPH-cytochrome P450 reductase and cytochrome P450 were reconstituted in microsomal phospholipid vesicles by cholate dialysis. The resulting membranes contained functional enzymes and did display enzymic lipid peroxidation induced by 75 microM NADPH and 10 microM Fe-EDTA (2:1). This model system was used to investigate whether microsomal glutathione transferase could inhibit lipid peroxidation in a glutathione-dependent manner. The results show that 5 mM glutathione did inhibit lipid peroxidation when functional microsomal glutathione transferase was included. This was not the case when the enzyme had been pre-inactivated with diethylpyrocarbonate. Furthermore, the protective effect of glutathione could be partly reversed by an inhibitor (100 microM bromosulphophtalein) of the enzyme. Apparently, rat liver microsomal glutathione transferase has the capacity to inhibit lipid peroxidation in a reconstituted system.

Amino Acid Sequence↗

PubMed1996

Ebselen inhibition of apoptosis by reduction of peroxides.

We investigated the capacity of ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one], a glutathione peroxidase mimic, to protect cells from radiation-induced apoptosis. Incubating mouse thymocytes with 25 microM ebselen immediately after 60Co gamma-radiation exposure (5 Gy) inhibited morphological changes associated with apoptosis. Treatment of thymocytes with ebselen before, during, or after irradiation completely blocked internucleosomal DNA fragmentation, a biochemical marker for apoptosis. We measured peroxides formed in cells during and after irradiation, using the oxidation-sensitive fluorescent probe 2',7'-dichlorofluorescin diacetate. By 2 min postirradiation, levels of peroxides in irradiated thymocytes were approximately 10-11 times greater than those in the same cells before irradiation, and levels continued to increase with time. We also measured membrane lipid peroxidation using cis-parinaric acid, a naturally fluorescent polyunsaturated fatty acid that readily incorporates into cell membranes. The oxidation of cis-parinaric acid also began soon after irradiation and increased with time. Peroxide generation and membrane lipid peroxidation preceded both internucleosomal DNA fragmentation and morphological changes characteristic of apoptosis. Treatment of cells with ebselen reduced peroxide levels and appeared to protect thymocytes from radiation-induced apoptosis by scavenging peroxides generated during and after irradiation. The results suggest that peroxide generation and membrane lipid peroxidation may be important signaling events that trigger apoptosis in irradiated cells.

Animals↗

PubMed1994

Iron induces lipid peroxidation in cultured macrophages, increases their ability to oxidatively modify LDL, and affects their secretory properties.

The present study demonstrates for the first time that iron ions can induce lipid peroxidation in intact macrophages without causing cell death. Macrophage lipid peroxidation increases cell-mediated oxidation of LDL, enhances the release of interleukin 1 and inhibits the release of apolipoprotein E from the macrophages. When cultured macrophages were exposed to ferrous ions (50 microM FeSO4) for 4 h at 37 degrees C, cellular lipid peroxidation (measured by analyses of malondialdehyde (MDA), conjugated dienes (CD), and lipid peroxides (PD)) increased 2-4-fold in comparison with non-treated cells. This process was iron-dose dependent, reached its maximum after 4 h of incubation, and was accompanied by 68% and 53% reductions in the content of the cellular linoleic (18:2), and arachidonic acid (20:4), respectively, and by 29% and 36% reductions of cellular vitamin E and vitamin A, respectively. Cell viability (measured by trypan blue exclusion, by [3H]thymidine incorporation into DNA, by analysis of the release of lactate dehydrogenase (LDH) or [3H]adenine), and cell morphology (studied by scanning electron microscopy) were not significantly affected by the iron-induced oxidative stress. Manitol and dimethylthiourea (DMTU), but not catalase or superoxide dismutase (SOD), significantly inhibited iron-induced cellular lipid peroxide formation, suggesting that hydroxyl radical, but not superoxides or hydrogen peroxides, mediated the iron-induced cellular lipid peroxidation. Incubation of LDL (0.2 mg of protein/ml) with oxidized macrophages resulted in LDL lipids peroxidation, as evidenced by an 8-fold increase in the LDL associated MDA in comparison with LDL that was incubated under similar conditions with non-oxidized macrophages. Furthermore, oxidation of LDL by oxidized macrophages in the presence of copper ions (10 microM CuSO4) was 2-fold higher in comparison with oxidation of LDL by non-oxidized macrophages. The release of apolipoprotein E from oxidized macrophages decreased by 50%, whereas macrophage release of beta-glucuronidase and of interleukin-1 beta increased by 83% and by a factor of 6, respectively. This study demonstrates for the first time that iron ions induce oxidation of the cellular polyunsaturated fatty acids in intact macrophages and that this cellular lipid peroxidation can subsequently induce LDL oxidation.

Animals↗

PubMed1989

Diastolic dysfunction of perfused rat hearts induced by hydrogen peroxide. Protective effect of selenium.

Oxidant substances such as hydrogen peroxide are postulated to cause cardiac dysfunction and injury in a number of pathological conditions. Selenium is an essential nutrient which serves as an oxidant defense through the selenoenzyme glutathione peroxidase. This enzyme metabolizes hydrogen peroxide; its activity in rat heart is reduced to 5% of control by selenium deficiency. Left ventricular function of selenium-deficient and control rat hearts was studied in a Langendorff preparation under isovolumic conditions. A stabilization period of 20 min was followed by a 70 min infusion of hydrogen peroxide at 375 or 1500 nmol/min. When no hydrogen peroxide was infused, perfusion for 90 min had no effect on systolic or diastolic function and no effect of selenium deficiency was detected. Hydrogen peroxide infusion into selenium-deficient hearts at 375 nmol/min led to impaired isovolumic relaxation and a substantial increase in end-diastolic pressure after 45 min which worsened progressively until the experiment was terminated. By contrast no effect was observed on systolic contractile function as assessed by peak pressure or developed pressure. Infusion of this dose of hydrogen peroxide into control hearts had no significant effect on diastolic or systolic function. However, infusion of 1500 nmol hydrogen peroxide/min into control hearts caused diastolic dysfunction after 30 min without affecting systolic function. These results indicate that hydrogen peroxide injury to the perfused rat heart is manifested by diastolic dysfunction before systolic dysfunction occurs. Selenium deficiency lowers the dose of hydrogen peroxide needed to cause diastolic dysfunction. This suggests that the selenoenzyme glutathione peroxidase protects the heart against hydrogen peroxide injury.

Animals↗

PubMed1983

Interaction of metals and carbon tetrachloride on lipid peroxidation and hepatotoxicity.

Rats were administered ferrous sulfate, cadmium chloride, or sodium vanadate alone and in combination with carbon tetrachloride (CCl4) to determine if lipid peroxidation is associated with the toxicity of the three metals and to determine if there is an interaction between these metals and CCl4 in producing lipid peroxidation and hepatotoxicity. Expired ethane was used as an index of lipid peroxidation while serum alanine aminotransferase (ALT) and histopathology were used to assess liver damage. Lipid peroxidation did not appear to be associated with the hepatotoxicity of cadmium since no measurable increase in ethane production was observed when serum ALT concentrations were doubled relative to controls. Cadmium did not increase ethane when administered with CCl4 and the increase in ALT was additive. Iron and vanadate produced small significant increases in ethane production but no increase in ALT and only minor histopathologic changes, yet potentiated lipid peroxidation and liver damage when administered with CCl4. Thus, Cd did not produce lipid peroxidation and did not potentiate the lipid peroxidation and hepatotoxicity of CCl4, while iron or vanadate which produced lipid peroxidation alone potentiated the lipid peroxidation and hepatotoxicity of CCl4.

Alanine Transaminase↗

PubMed1990

Characterization of the hydrogen peroxide-enzyme reaction for two cytochrome c peroxidase mutants.

The bimolecular reaction between Escherichia coli-produced cytochrome-c peroxidase (CcP(MI)) and hydrogen peroxide is identical to that of native yeast cytochrome-c peroxidase (CcP) and hydrogen peroxide in the neutral pH region. Both enzymes have pH-independent bimolecular rate constants of 46 microM-1.s-1 for the reaction with hydrogen peroxide. A second mutant enzyme, E. coli-produced cytochrome-c peroxidase mutant with phenylalanine at position 191 (CcP(MI, F191)), has a pH-independent bimolecular rate constant for the hydrogen peroxide reaction of 65 microM-1.s-1, 40% larger than for CcP or CcP(MI). The initial peroxide-oxidation product of CcP(MI, F191) is an oxyferryl porphyrin pi-cation radical intermediate in contrast to the oxyferryl amino-acid radical intermediate formed upon oxidation of CcP or CcP(MI) with hydrogen peroxide. The reactions of all three enzymes with hydrogen peroxide are pH-dependent in KNO3-containing buffers. The reactions are influenced by an ionizable group, which has an apparent pKa of 5.4 in all three enzymes. The enzymes react with hydrogen peroxide when the ionizable group is unprotonated. Both CcP(MI) and CcP(MI, F191) have slightly smaller pH stability regions compared to CcP as assessed by the hydrogen peroxide titer and spectral analysis. The alteration in structural stability must be attributed to differences in the primary sequence between CcP and CcP(MI) which occur at positions -2, -1, 53 and 152.

Cytochrome-c Peroxidase↗

PubMed1995

Topical hydrogen peroxide treatment of ischemic ulcers in the guinea pig: blood recruitment in multiple skin sites.

BACKGROUND: Oxygen deficit is a key factor associated with delayed healing of ischemic wounds in human beings. Topical oxygen-releasing compounds such as hydrogen peroxide or tetrachlorodecaoxide have been suggested as therapy for ischemic tissue. OBJECTIVE: Our purpose was to monitor the effect of hydrogen peroxide cream on the process of ischemic ulcer healing with a model for ischemic ulcers in the guinea pig. METHODS: Measurement of vascular perfusion with a laser Doppler velocimeter and gross observations of percentage of nonnecrotic wound surface were made on ischemic wounds in guinea pigs after treatment with either a hydrogen peroxide cream or a placebo cream. RESULTS: Visual evaluations of the percentage of nonnecrotic wound surface showed no statistically significant differences among the treatments. In contrast, vascular perfusion measurements resulted in statistically significant differences. Blood flow was significantly higher up to day 15 in ulcers treated with 2% hydrogen peroxide cream than in those treated with placebo cream. Vascular perfusion was significantly higher in ulcers treated with 3.5% hydrogen peroxide cream than in ulcers treated with either 1.5% hydrogen peroxide cream or placebo. Adjacent control sites in guinea pigs whose ulcers were treated with hydrogen peroxide cream showed increased vascular perfusion compared with corresponding sites in animals whose ulcers were treated with placebo. Even distant flank control sites of ulcers treated with 3.5% hydrogen peroxide cream showed increased vascular perfusion. CONCLUSION: Treatment of ischemia-induced ulcers with hydrogen peroxide cream enhanced cutaneous blood recruitment not only to ulcers and adjacent sites, but also to distant sites.

Administration, Cutaneous↗

PubMed1987

Stimulation of cyclophosphamide-induced pulmonary microsomal lipid peroxidation by oxygen.

Cyclophosphamide (CP) causes lung toxicity in a wide variety of animals including humans. Recent reports suggest that CP increases lipid peroxide formation in the lung, and that oxygen (O2) potentiates CP-induced lung toxicity. We hypothesized that CP, or one of its toxic metabolites, acrolein, stimulates lung lipid peroxide formation in the presence of high O2 tensions. To test this, rat lung microsomes were treated in vitro with CP or acrolein in the presence of NADPH and 0-100% O2 with and without superoxide dismutase (SOD), glutathione (GSH), dithiothreitol (DTT), and EDTA (agents which scavenge reactive O2 species and/or detoxify reactive metabolites). Lipid peroxide formation in untreated microsomes was increased 40, 39, and 37% in 60, 80 and 100% O2 respectively (P less than 0.02 vs. 21% O2 air). Lipid peroxide formation in microsomes treated with CP increased 2-3-fold under 21% O2 (P less than 0.05 vs. untreated under 21% O2). However, increases in lipid peroxide formation were 3-4 fold in CP treated microsomes under 40-100% O2 (P less than 0.001 vs. untreated at same % O2). CP and acrolein-stimulated lipid peroxidation with and without O2 exposure was significantly (P less than 0.05) reduced by prior addition of SOD, GSH, DTT, or EDTA to the lung microsomal suspension. These results indicate that lipid peroxide formation increases in CP and acrolein-treated lung microsomes, and high O2 tensions stimulate CP-induced lipid peroxidation. Stimulation of CP-induced microsomal lipid peroxidation appears to be mediated by reactive O2 species or metabolites.

Acrolein↗

PubMed1987

Peroxide alters neuronal excitability in the CA1 region of guinea-pig hippocampus in vitro.

Effects of peroxidative damage on neuronal excitability were investigated with electrophysiological techniques in CA1 pyramidal cells of the hippocampal slice preparation. Hydrogen peroxide alone or combined with ferrous ions (peroxide/iron) is likely to produce hydroxyl free radicals through the Fenton reaction. Intracellularly recorded excitatory postsynaptic potentials and inhibitory postsynaptic potentials were significantly reduced by exposure to peroxide, while responses to iontophoretically applied GABA and glutamate were unaffected. These results suggest that peroxide has presynaptic actions. Peroxide and peroxide/iron also increased frequency adaptation; after exposure, neurons fired fewer action potentials at a lower frequency in response to the same depolarizing current step. A voltage clamp analysis revealed that the potassium currents were unaffected by peroxide/iron. Calcium current was not obviously altered by exposure to peroxide. Sodium spike threshold was also unaffected. Calcium spike threshold was significantly increased by peroxide. This action of peroxide may underlie its presynaptic actions. It is concluded that peroxide produces both presynaptic and postsynaptic damage. This damage is likely to result from the production of free radicals which have been postulated to underlie a number of pathological states.

Action Potentials↗

PubMed1985

Phospholipase A2 dependent release of fatty acids from peroxidized membranes.

Unilamellar vesicles (liposomes) consisting of liver phosphatidylcholine and phosphatidylethanolamine were used as model membranes and subjected to lipid peroxidation. Following peroxidation samples were treated with phospholipase A2 from snake venom and subsequently analyzed for products of lipid peroxidation and of phospholipase A2 action. A significantly increased susceptibility to phospholipase A2 was noted for liposomes subjected to peroxidation, as compared to controls, which correlated with the extent of lipid peroxidation measured by the formation of thiobarbituric acid reacting products and conjugated dienes. Low levels of peroxides were detected in control liposomes and these peroxidases were rapidly cleaved by phospholipase A2, such that nearly 40% of the total peroxide content was associated with free fatty acids after l5 min incubation. Oxidized liposomes contained over seven fold the level of lipid peroxidation products, and the were also rapidly cleaved by phospholipase A2 where over 50% were recovered as free fatty acids following l5 min of exposure to phospholipase A2. Along with this high order of removal of oxidized fatty acids, a marked hydrolysis of intact fatty acids was also observed. The extent of fatty acid release was roughly correlated with the degree of fatty acid unsaturation. A substantial increase in the release of arachidonic acid was found when peroxidized membranes were analyzed.

Fatty Acids↗

PubMed1990

Simulation of free radical reactions in biology and medicine: a new two-compartment kinetic model of intracellular lipid peroxidation.

To explore mechanisms of free radical reactions leading to intracellular lipid peroxidation in living systems, we developed a computational model of up to 109 simultaneous enzymatic and free radical reactions thought to be involved in the initiation, propagation, and termination of membrane lipid peroxidation. Rate constants for the various reactions were obtained from the published literature. The simulation model included a lipid membrane compartment and an aqueous cytosolic compartment, between which various chemical species were partitioned. Lipid peroxidation was initiated by the iron-catalyzed, superoxide-driven Fenton reaction. A "C" language computer program implemented numerical solution of the steady-state rate equations for concentrations of nine relevant free radicals. The rate equations were integrated by a modified Euler technique to describe the evolution with time of simulated concentrations of hydrogen peroxide, ferric and ferrous iron, unsaturated lipid, lipid hydroperoxides, superoxide anion, and biological antioxidants, including SOD and catalase. Initial results led to significant insights regarding mechanisms of membrane lipid peroxidation: 1. segregation and concentration of lipids within membrane compartments promotes chain propagation; 2. in the absence of antioxidants computed concentrations of lipid hydroperoxides increase linearly about 40 microM/min during oxidative stress; 3. lipid peroxidation is critically dependent upon oxygen concentration and the modeled dependence is similar to the experimental function; 4. lipid peroxidation is rapidly quenched by the presence of Vitamin E-like antioxidants, SOD, and catalase; 5. only small (1 to 50 microM) amounts of "free" iron are required for initiation of lipid peroxidation; 6. substantial lipid peroxidation occurs only when cellular defense mechanisms have been weakened or overcome by prolonged oxidative stress, hence understanding of the balance between free radical generation and antioxidant defense systems is critical to the understanding and control of free radical reactions in biology and medicine.

Antioxidants↗

PubMed1996

Pyrene lipids as markers of peroxidative processes in different regions of low and high density lipoproteins.

Three different pyrene derivatives, pyrene decanoyl phosphatidylcholine (P10PC), pyrene dodecanoyl sulfatide (P12CS) and cholesteryl pyrenyl hexanoate (P6Chol), were used to follow lipid peroxidation in low and high density lipoproteins. Probe-labelled lipoproteins were subjected to Cu2+ catalyzed peroxidation. In all cases the fluorescence of the probes progressively decreased due to the involvement of pyrene in the peroxidative reaction. Thus, we used the fluorescence decrease of P6Chol to monitor the lipid peroxidation in the hydrophobic core of LDL and HDL, and that of the amphipatic probes, P10PC and P12CS, to follow lipid peroxidation in the envelope of both lipoproteins. The possibility of following lipid peroxidation in individual lipoprotein regions could lead to more detailed information on the oxidative modifications that play an important role in the altered cholesterol homeostasis involved in the formation of atherosclerotic lesions. No differences were observed in the peroxidation kinetics of the hydrophobic core of HDL and LDL monitored with P6Chol. On the contrary kinetics obtained with P10PC and P12 CS demonstrated the HDL envelope to be more susceptible to Cu2+ -dependent lipid peroxidation than that of the LDL. This could be due to a greater radical generating capacity of the HDL envelope and can be explained on the basis of low vitamin E levels and large amounts of polyunsaturated fatty acids esterified on phospholipids determined in HDL, and on literature evidence that indicates HDL as the principal vehicle of circulating plasma lipids peroxides.

Adult↗