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PubMed2001

Lupeol, a triterpene, inhibits early responses of tumor promotion induced by benzoyl peroxide in murine skin.

The modulating effect of Lupeol [lup-20(29)-en-3 beta -ol], a triterpene found in many fruits and medicinal plants, on benzoyl peroxide-induced tumor promotion responses or tumor promotion in murine skin is described. Benzoyl peroxide is an effective cutaneous tumor promoter acting through the generation of oxidative stress, the induction of ornithine decarboxylase activity and the enhancement of DNA synthesis. Benzoyl peroxide treatment increases cutaneous microsomal lipid peroxidation and hydrogen peroxide generation. The activity of the cutaneous antioxidant enzymes, namely catalase, glutathione peroxidase, glutathione reductase and glutathione S-transferase, is decreased and levels of cutaneous glutathione are depleted. Benzoyl peroxide treatment also induces ornithine decarboxylase activity and enhances [3H]thymidine uptake in DNA synthesis. Prophylactic treatment of mice with lupeol (0.75 and 1.5 mg per animal) 1 hour before benzoyl peroxide treatment resulted in a diminution of benzoyl peroxide-mediated damage. The susceptibility of cutaneous microsomal membrane to lipid peroxidation and hydrogen peroxide generation was significantly reduced (P< 0.01 and P< 0.01, respectively). In addition, depleted levels of glutathione and inhibited activity of antioxidant enzymes were recovered to a significant level (P< 0.01, P< 0.05 and P< 0.01, respectively). Similarly, the elevated ornithine decarboxylase activity and enhanced thymidine uptake in DNA synthesis were inhibited significantly (P< 0.05) in a dose-dependent manner. The protective effect of lupeol was dose dependent in all parameters. The results suggest that lupeol is an effective skin chemopreventive agent that may suppress benzoyl peroxide-induced cutaneous toxicity.

Animals↗
PubMed2005

New assays for detection and localization of endogenous lipid peroxidation products in living boar sperm after BTS dilution or after freeze-thawing.

Reactive oxygen species have been implicated in sperm aberrations causing multiple pathologies including sub- and infertility. Freeze/thawing of sperm samples is routinely performed in the cattle breeding industries for semen storage prior to artificial insemination but unusual in porcine breeding industries as semen dilution and storage at 17 degrees C is sufficient for artificial insemination within 2-3 days. However, longer semen storage requires cryopreservation of boar semen. Freeze/thawing procedures induce sperm damage and induce reactive oxygen species in mammalian sperm and boar sperm seems to be more vulnerable for this than bull sperm. We developed a new method to detect reactive oxygen species induced damage at the level of the sperm plasma membrane in bull sperm. Lipid peroxidation in freshly stored and frozen/thawed sperm cells was assessed by mass spectrometric analysis of the main endogenous lipid classes, phosphatidylcholine and cholesterol and by fluorescence techniques using the lipid peroxidation reporter probe C11-BODIPY(581/591). Peroxidation as reported by the fluorescent probe, clearly corresponded with the presence of hydroxy- and hydroperoxyphosphatidylcholine in the sperm membranes, which are early stage products of lipid peroxidation. This allowed us, for the first time, to correlate endogenous lipid peroxidation with localization of this process in the living sperm cells. Cytoplasmatic droplets in incompletely matured sperm cells were intensely peroxidized. Furthermore, lipid peroxidation was particularly strong in the mid-piece and tail of frozen/thawed spermatozoa and significantly less intense in the sperm head. Induction of peroxidation in fresh sperm cells with the lipid soluble reactive oxygen species tert-butylhydroperoxide gave an even more pronounced effect, demonstrating antioxidant activity in the head of fresh sperm cells. Furthermore, we were able to show using the flow cytometer that spontaneous peroxidation was not a result of cell death, as only a pronounced subpopulation of living cells showed peroxidation after freeze-thawing. Although the method was established on bovine sperm, we discuss the importance of these assays for detecting lipid peroxidation in boar sperm cells.

Animals↗
PubMed1995

Hydrogen peroxide induces 21-aminosteroid-inhibitable F2-isoprostane production and cytolysis in renal tubular epithelial cells.

F2-isoprostanes are the newly identified reactive oxygen species-catalyzed peroxidation products of arachidonate. The infusion of these prostaglandin F2-like prostanaoids into the rat kidney induces profound parallel reductions in RBF and GFR, suggesting that these metabolites may be partly responsible for the hemodynamic alterations seen in free radical-linked acute renal injury models. The present study examined directly in renal proximal tubular (LLC-PK1) cells whether hydrogen peroxide, a reactive oxygen species implicated in many models of acute renal injury, induces F2-isoprostane production and whether its production can be inhibited by the recently synthesized lipid peroxidation inhibitor 21-aminosteroid (lazaroid U-74389G). The incubation of LLC-PK1 cell layers with hydrogen peroxide for 3 h resulted in a dose-related six-fold increase in F2-isoprostane production, measured by the gas chromatographic-mass spectroscopic method. The preincubation of cells with 21-aminosteroid prevented hydrogen peroxide-induced F2-isoprostane production, a finding also demonstrable with other lipid peroxidation inhibitors, e.g., 2-methyl aminochroman (U-83836E) and diphenyl-p-phenylenediamine. Besides inhibiting isoprostane production, 21-aminosteroid reduced hydrogen peroxide-induced lipid degradation and peroxidation, and protected the cells against hydrogen peroxide-induced cytolysis. The novel finding that hydrogen peroxide induces 21-aminosteroid-inhibitable F2-isoprostane production in renal epithelial cells supports the in vivo report that its levels are elevated in reactive oxygen species-linked renal injury models such as ischemia-reperfusion. Besides direct cell injury, lipid peroxidation by generating F2-isoprostanes may further contribute to renal dysfunction through a vasoconstrictive mechanism. Thus, the inhibition of excess F2-isoprostane production may be one of the additional mechanisms, besides cytoprotection, by which antioxidants ameliorate renal dysfunction in experimental models of acute renal injury.

Animals↗
PubMed1996

Protective action of dehydroascorbic acid on the Ah receptor-dependent and receptor-independent induction of lipid peroxidation in adipose tissue of male guinea pig caused by TCDD administration.

The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on lipid peroxidation, 3H-Me-glucose (3H-Me-glu), and 14C-dehydroascorbic acid (14C-DHA) uptakes were studied in adipose tissue of male guinea pig. Under in vitro test conditions, using isolated adipose tissue in a culture medium (explant culture), TCDD reduced the uptake of 3H-Me-glu and 14C-DHA in a dose- and time-dependent fashion. The IC50 values of TCDD's action were 0.04 and 2 nM on 14C-DHA and 3H-Me-glu uptakes, respectively. TCDD (10 nM) also suppressed glucose transporting activity within 15 minutes in explant-cultured adipocytes. Cytochalasin B (CB) and nonlabeled D-glucose inhibited 14C-DHA uptake also in a dose-dependent manner. In addition, TCDD was found to induce lipid peroxidation in explant-cultured adipose tissue. This effect of TCDD was similar to that of a typical lipid peroxidation inducer, CCl4, and it was dose and time dependent. TCDD caused a statistically significant rise in lipid peroxidation at a concentration as low as 0.1 nM after 60 minutes of treatment in explant culture. Unexpectedly, the Ah receptor partial antagonists, 4,7-phenanthroline and alpha-naphthoflavone, did not fully antagonize TCDD-induced lipid peroxidation in explant-cultured adipocytes. In vivo treatment of TCDD also induced lipid peroxidation. Among seven organs of male guinea pig tested, the levels of lipid peroxidation in adipose tissue and in liver increased at 1 and 40 days following a single i.p. dose of TCDD (1 microgram/kg). The results of an in vivo time-course study indicated that such an effect of TCDD was most pronounced after 40 days of treatment. Finally, we have tested the protective role of some antioxidants on TCDD-induced lipid peroxidation under explant-culture conditions. The results indicated that DHA, but not ascorbic acid, could completely abolish TCDD-induced lipid peroxidation. The protective effect of DHA on TCDD-induced lipid peroxidation was stronger than that of alpha-tocopherol and uric acid, and this effect was blocked by CB. We conclude from these studies that TCDD acts in this guinea pig tissue through two different routes: one is the Ah receptor-dependent route causing the reduction of the level of glucose transporters and subsequent decrease of cellular uptake of DHA and the other, the Ah receptor-independent route causing the overall lipid peroxidation. Nevertheless, it appears likely that both events are antagonized by DHA.

Adipose Tissue↗
PubMed2002

Peroxide formation in polysorbate 80 and protein stability.

Nonionic surfactants are widely used in the development of protein pharmaceuticals. However, the low level of residual peroxides in surfactants can potentially affect the stability of oxidation-sensitive proteins. In this report, we examined the peroxide formation in polysorbate 80 under a variety of storage conditions and tested the potential of peroxides in polysorbate 80 to oxidize a model protein, IL-2 mutein. For the first time, we demonstrated that peroxides can be easily generated in neat polysorbate 80 in the presence of air during incubation at elevated temperatures. Polysorbate 80 in aqueous solution exhibited a faster rate of peroxide formation and a greater amount of peroxides during incubation, which is further promoted/catalyzed by light. Peroxide formation can be greatly inhibited by preventing any contact with air/oxygen during storage. IL-2 mutein can be easily oxidized both in liquid and solid states. A lower level of peroxides in polysorbate 80 did not change the rate of IL-2 mutein oxidation in liquid state but significantly accelerated its oxidation in solid state under air. A higher level of peroxides in polysorbate 80 caused a significant increase in IL-2 mutein oxidation both in liquid and solid states, and glutathione can significantly inhibit the peroxide-induced oxidation of IL-2 mutein in a lyophilized formulation. In addition, a higher level of peroxides in polysorbate 80 caused immediate IL-2 mutein oxidation during annealing in lyophilization, suggesting that implementation of an annealing step needs to be carefully evaluated in the development of a lyophilization process for oxidation-sensitive proteins in the presence of polysorbate.

Air↗
PubMed1998

A fluorescence plate reader assay for monitoring the susceptibility of biological samples to lipid peroxidation.

The susceptibility of biological samples to lipid peroxidation can be determined by exposing samples to a lipid peroxidation initiator and measuring the length of time prior to the onset of lipid peroxidation. Previous studies have shown that aldehydes generated by lipid peroxidation can react with amines to produce fluorescent products. We have utilized this principle to develop a fluorescence plate reader assay for measuring susceptibility to lipid peroxidation. In this assay, samples are placed in glycine/phosphate buffer and loaded into a 96-well plate. Lipid peroxidation initiators are added, and fluorescence is monitored over time. Samples were assayed for susceptibility to lipid peroxidation by both the thiobarbituric acid reactive substances assay and the fluorescence plate reader assay. We found good agreement between these two methods in assessing relative susceptibility to lipid peroxidation in liver microsomes and mitochondria. The fluorescence assay was also used to monitor lipid peroxidation in liposomes and rat liver homogenates. Fluorescence was stable over an extended time period and could be induced by a variety of lipid peroxidation initiators. The fluorescence plate reader assay offers a rapid method for monitoring lipid peroxidation in a large number of samples.

Animals↗
PubMed1988

Analysis of cardiac membrane phospholipid peroxidation kinetics as malondialdehyde: nonspecificity of thiobarbituric acid-reactivity.

When exposed to xanthine oxidase (superoxide)-dependent, iron-promoted Fenton chemistry, purified cardiac membranes evidenced, by the thiobarbituric acid (TBA) test, a virtually instantaneous peroxidative response with a maximal linear rate of 5.8 nmol malondialdehyde (MDA)-equivalents/mEquivalents lipid ester reacted/min. Yet when the lipids purified from these same membranes and reconstituted into liposomes were peroxidized under identical reaction conditions, the TBA test indicated that a pronounced (approximately 20-min) lag period preceded a maximal peroxidation rate of only 2.1 nmol MDA-equivalents/mEquivalents lipid ester reacted/min. After 120 min of peroxidation, the cardiac membranes yielded some 300 nmol TBA-reactive MDA-equivalents/mEquivalent ester, whereas the isolated membrane lipids evidenced approximately 40% less TBA-reactivity. To verify that these quantitative and kinetic differences in membrane (phospho)-lipid peroxidation occurred with removal of the lipids from their membrane milieu, the MDA produced during both cardiac membrane peroxidation and the peroxidation of the lipids derived therefrom was isolated as its free anion by ion-pair high-pressure liquid chromatography. As quantified spectrophotometrically, true MDA production during myocardial membrane peroxidation was identical in kinetics and in amount to the production of TBA-reactive substance from the peroxidized isolated membrane lipids. These results demonstrate that significant non-MDA, TBA-reactive species are generated during the peroxidation of cardiac membranes, especially before the maximal rates of bona fide MDA production. As a direct consequence, artifactual levels and kinetics of membrane lipid peroxidation do result.

Animals↗
PubMed1988

Promotion of iron-induced rat liver microsomal lipid peroxidation by copper.

Although copper has been demonstrated to promote lipid peroxidation in a number of systems, the mechanisms involved have not been fully defined. In this study, the role of copper in modifying lipid peroxidation has been explored in rat hepatic microsomes. In an in vitro system containing reduced glutathione (GSH, 200 microM) and Tris buffer, pH 7.4, cupric sulfate (1-50 microM) potentiated lipid peroxidation induced by ferrous sulfate (10 microM) but was unable to elicit peroxidation in the absence of iron. Higher levels of cupric sulfate (100 microM or greater) were inhibitory. The nature as well as the extent of the peroxidative response of microsomes to cupric sulfate were dependent on glutathione levels in addition to those of iron. Cupric sulfate (100 microM) strongly potentiated ferrous ion-induced lipid peroxidation in the presence of 400-800 microM GSH, while it inhibited peroxidation at lower levels of GSH (0-200 microM) and did not affect ferrous ion-induced peroxidation with glutathione levels of 3-10 mM. The potentiating effect of copper on ferrous ion-induced lipid peroxidation was further explored by investigating: (1) potential GSH-mediated reduction of cupric ions; (2) potential copper/GSH-mediated reduction of ferric ions (formed by oxidation during incubation); and (3) possible promotion of propagation reactions by copper/GSH. Our results indicate that cupric ions are reduced by GSH and thus are converted from an inhibitor to an enhancer of iron-induced lipid peroxidation. Cuprous ions appear to potentiate lipid peroxidation by reduction of ferric ions, rather than by promoting propagation reactions. Iron (in a specific Fe+2/Fe+3 ratio) is then an effective promoter of initiation reactions.

Animals↗
PubMed1980

Glutathione-dependent inhibition of lipid peroxidation by a soluble, heat-labile factor in animal tissues.

A glutathione-dependent, cytosolic factor (previously thought to be glutathione peroxidase), inhibits lipid peroxidation in both microsomal and mitochondrial membranes. Studies in this laboratory had shown that the inhibition was due to prevention of peroxidative attack on the polyunsaturated fatty acids in the membrane lipids even under conditions that would otherwise promote rapid lipid peroxidation. A glutathione-dependent factor is also present in rat liver cytosol which can utilize peroxides of both free fatty acid salts in solution and free fatty acids in micellar suspension as substrates. It does not, however, utilize peroxidized lipids of microsomal and mitochondrial membranes as substrates. Whether or not this is the same factor which inhibits lipid peroxidation is not known with certainty, but current information indicates that they are not the same. Data presented in this report support the conclusion that neither glutathione peroxidase nor glutathione S-transferase activities appear to be responsible for the inhibition of lipid peroxidation in biological membranes. After partial purification of active preparations of both of these peroxidases, it was observed that neither preparation inhibited lipid peroxidation. The results of this study further support the conclusion that the glutathione-dependent cytosolic factor which inhibits lipid peroxidation in biological membranes does so by preventing the peroxidation rather than by reducing lipid peroxides.

Animals↗
PubMed1985

Aluminium salts accelerate peroxidation of membrane lipids stimulated by iron salts.

Aluminium salts do not themselves stimulate peroxidation of ox-brain phospholipid liposomes, but they greatly accelerate the peroxidation induced by iron(II) salts at acidic pH values. This effect of Al(III) is not seen at pH 7.4, perhaps because Al(III) salts form insoluble complexes at this pH in aqueous solution. Peroxidation of liposomes in the presence of Al(III) and Fe(II) salts is inhibited by the chelating agent desferrioxamine, and by EDTA and diethylenetriaminepentaacetic acid at concentrations greater than those of Fe(II) salt. Aluminium salts slightly stimulate the peroxidation of peroxide-depleted linolenic acid micelles, but they do not accelerate the peroxidation induced by addition of iron(II) salts to the micelles at acidic pH. Aluminium salts accelerate the peroxidation observed when human erythrocytes are treated with hydrogen peroxide at pH 7.4. Desferrioxamine decreases the peroxidation. We suggest that Al(III) ions produce an alteration in membrane structure that facilitates lipid peroxidation, and that the increased formation of fluorescent age pigments in the nervous system of patients exposed to toxic amounts of Al(III) may be related to this phenomenon. The ability of desferal to bind both iron (III) and aluminium(III) salts and to inhibit lipid peroxidation makes it an especially useful chelating agent in the treatment of 'aluminium overload'.

Aluminum↗
PubMed1988

Lipid peroxidation of rabbit small intestinal microvillus membrane vesicles by iron complexes.

Fe(II)- and Fe(III)-induced lipid peroxidation of rabbit small intestinal microvillus membrane vesicles was studied. Ferrous ammonium sulphate, ferrous ascorbate at a molar ratio of 10:1, and ferric citrate, at molar ratios of 1:1 and 1:20, did not stimulate lipid peroxidation. Ferrous ascorbate, 1:1, induced low stimulation, while ferrous ascorbate, 1:20 gave higher stimulation of lipid peroxidation. These results show that in our experimental system, ascorbate is a promotor rather than an inhibitor of lipid peroxidation. Ferric nitrilotriacetate (at molar ratios of 1:2 and 1:10), at an iron concentration of 200 microM, was by far the most effective in inducing lipid peroxidation. Superoxide dismutase, mannitol and glutathione had no effect, while catalase, thiourea and vitamin E markedly decreased ferrous ascorbate 1:20-induced lipid peroxidation. Ferric nitrilotriacetate-induced lipid peroxidation was slightly reduced by catalase and mannitol, significantly reduced by superoxide dismutase, and completely inhibited by thiourea. Glutathione caused a 100% increase in the ferric nitrilotriacetate-induced lipid peroxidation. These results suggest that Fe(II) in the presence of trace amounts of Fe(III), or an oxidizing agent and Fe(III) in the presence of Fe(II) or a reducing agent, are potent stimulators of lipid peroxidation of microvillus membrane vesicles. Addition of deferoxamine completely inhibited both ferrous ascorbate, 1:20 and ferric nitrilotriacetate-induced lipid peroxidation, demonstrating the requirement for iron for its stimulation. Iron-induced peroxidation of microvillus membrane may have physiological significance because it could already be demonstrated at 2 microM iron concentration.

Animals↗
PubMed1989

Interaction of lipid peroxidation products with nuclear macromolecules.

The interaction of lipid peroxidation products with nuclear macromolecules was investigated in rat liver nuclei labelled with [3H]arachidonic acid. Lipid peroxidation reactions were driven both non-enzymatically and enzymatically by the addition of ascorbate-Fe2+ or NADPH-ADP-Fe3+, respectively, to the incubation mixtures. The extent of peroxidation was evaluated by the formation of thiobarbituric acid chromophore and of radioactive hydrophilic peroxidation products. The results obtained show that: (1) nuclear membrane lipid peroxidation products formed during incubation interact with DNA and total nuclear proteins; (2) non-enzymatic lipid peroxidation processes induced a 40% larger association of peroxidation products to DNA compared to processes driven enzymatically, whereas the corresponding interaction with total nuclear proteins was similar in both peroxidation systems; (3) the radioactivity associated with histones decreased during incubation in the presence of ascorbate-Fe2+ or NADPH-ADP-Fe3+, and increased in control samples (no additions); (4) inhibition of lipid peroxidation by the iron chelator Desferrioxamine B prevented the association of peroxidation products to nuclear macromolecules; (5) the levels of radioactivity found in DNA after 180 min of incubation would represent the formation of 0.6-1.0 adducts per 10(6) DNA bases. The results obtained provide evidence for an interaction between lipid peroxidation products and chromatin in the interior of the cell nucleus.

Animals↗
PubMedDate not supplied

Age-related decline in multiple unit action potentials of CA3 region of rat hippocampus: correlation with lipid peroxidation and lipofuscin concentration and the effect of centrophenoxine.

Changes in lipid peroxidation, lipofuscin concentration, and multiple unit activity (MUA recorded in conscious animals) in the CA3 region were studied in the hippocampus of male Wistar rats aged 4, 8, 16, and 24 months. The lipid peroxidation and lipofuscin concentration were increased with age. The MUA, however, declined with age. Correlational analyses were performed for the four age groups to determine the relationship between the age-associated decline in MUA with the age-related alterations in lipid peroxidation and lipofuscin concentrations. The age-related increase in lipid peroxidation correlated positively with the age-associated increase in lipofuscin concentration. The age-related increases in lipid peroxidation and lipofuscin concentration correlated negatively with the changes in MUA. Since lipid peroxidation may affect neuronal electrophysiology, our data suggested that age-related increase in lipid peroxidation may contribute to an age-associated decline in neuronal electrical activity. Centrophenoxine effects were studied on the three above-mentioned age-associated changes in the hippocampus. The drug had no effect on all three parameters in 4- and 8-month-old rats. In 16- and 24-month-old rats, however, the drug significantly increased the MUA but concomitantly decreased lipofuscin concentration and lipid peroxidation. Correlational analyses of the data on MUA, lipid peroxidation and lipofuscin concentration from the centrophenoxine-treated animals showed that the drug-induced diminution in both lipofuscin and lipid peroxidation was significantly correlated with the drug-induced increase in MUA. The differential effect of the drug in younger (4-8 months) and older (16-24 months) animals indicated that the stimulation of MUA was clearly associated with concomitant decrease in lipid peroxidation and lipofuscin concentration.

Action Potentials↗
PubMed1992

Effect of lipid physical state on the rate of peroxidation of liposomes.

The effect of cholesterol on the rate of peroxidation of arachidonic acid and 1-palmitoyl-2-arachidonoyl phosphatidylcholine (PAPC) in dimyristoylphosphatidylcholine (DMPC) liposomes was examined above and below the phase transition temperature (Tm) of the lipid. The rate of peroxidation of arachidonic acid was more rapid below the phase transition temperature of the host lipid. At a temperature below the Tm (4 degrees C), increasing concentrations of cholesterol reduced the rate of peroxidation of arachidonic acid as judged by the production of thiobarbituric acid reactive substances. Above Tm (37 degrees C), cholesterol increased the rate of peroxidation of the fatty acid. Similarly, PAPC was peroxidized more rapidly at 4 degrees C than at 37 degrees C. However, cholesterol had little effect on the rate of peroxidation of PAPC at 4 degrees C. The rate of peroxidation of arachidonic acid was related to the lipid bilayer fluidity as judged by fluorescence anisotropy measurements of diphenylhexatriene. The rate of peroxidation increased slowly with increasing rigidity of the probe environment when the bilayer was relatively fluid and more rapidly as the environment became more rigid. The increase in the rate of peroxidation of arachidonic acid in the less fluid host lipid was unrelated to differences in iron binding or to transfer of arachidonic acid to the aqueous phase. Decreasing the concentration of arachidonic acid in DMPC to less than 2 mol% dramatically decreased the rate of peroxidation at 4 degrees C, suggesting that formation of clusters of fatty acids at 4 degrees C is required for rapid peroxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Arachidonic Acids↗
PubMed1998

Comparison of the effects of hydrogen peroxide, 4-hydroxy-2-nonenal and beta-amyloid (25-35) upon calcium signalling.

The neurotoxic beta-amyloid (Abeta) peptide fragment Abeta(25-35) has been suggested to exert its deleterious effects on cells via production of hydrogen peroxide. In human platelets and in the presence of DMSO to prevent production of hydroxyl radicals from hydrogen peroxide, both Abeta(25-35) and hydrogen peroxide were found to increase intracellular calcium levels. Hydrogen peroxide in addition reduced the calcium response to thrombin, whereas this was not seen with Abeta(25-35). A similar pattern of effects to those seen with hydrogen peroxide were also seen with the neurotoxic aldehyde lipid peroxidation product 4-hydroxy-2-nonenal (HNE). The initial increase in calcium produced by hydrogen peroxide was not affected by EGTA, but was partially prevented by dithiothreitol. The calcium response to Abeta(25-35) [which was also seen with Abeta(1-40) and Abeta(1-42) but not with the inactive peptide Abeta(40-1)] consisted of an EGTA-sensitive and an EGTA-resistant component, of which the latter was also sensitive to DTT. Hydrogen peroxide increased basal phosphoinositide breakdown in rat brain miniprisms and decreased the responses to noradrenaline, carbachol and veratrine. The specific binding of [3H]inositol-1,4,5-trisphosphate ([3H]Ins(1,4,5)P3) to its receptor recognition site in human platelet membranes was increased by Abeta(25-35) but remained unchanged following hydrogen peroxide treatment. It is concluded that under conditions where production of hydroxyl radicals from hydrogen peroxide is blocked, hydrogen peroxide and Abeta(25-35) produce their effects on calcium by affecting the mobilisation of intracellular calcium. The qualitative differences in the calcium responses of these two agents can be explained (a) by an additional effect of Abeta(25-35) upon calcium entry and (b) by differences in their effects upon the Ins(1,4,5)P3 receptor.

Aldehydes↗
PubMed1998

HTHQ (1-O-hexyl-2,3,5-trimethylhydroquinone), an anti-lipid-peroxidative compound: its chemical and biochemical characterizations.

Recently, it has become apparent that reactive oxygen species (ROS) play many important roles in biological systems. For example, relationships between many diseases, such as cancer, cardiac infarction and arteriosclerosis, and ROS have been found. It is also well known that anti-oxidative agents scavenge ROS in biological systems, which in turn prevents ROS-related diseases. In our previous efforts to develop effective anti-oxidative compounds, we found that 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), which is a hydroquinone monoalkyl ether, is a potent anti-oxidative agent. Here, the scavenging activities of HTHQ against ROS, such as superoxide anion radicals, hydroxyl radicals, t-butyl peroxyl radicals and singlet oxygens, were examined by the ESR (electron spin resonance)-spin trapping method. Among ROS, HTHQ scavenged t-butyl peroxyl radicals most effectively (IC50=0.31+/-0.04 mM), showing approximately twice the activity of a well-known lipophilic anti-oxidant, D,L-alpha-tocopherol (IC50=0.67+/-0.06 mM), as measured by IC50 values defined as the 50% inhibition concentration of the generated ROS. In addition, a relatively stable ESR spectrum of free radicals due to HTHQ was observed during the reaction of HTHQ and t-butyl peroxyl radicals, indicating a direct reaction of HTHQ and t-butyl peroxyl radicals. The free radicals due to HTHQ were more stable than those derived from D,L-alpha-tocopherol under the same conditions examined. On the basis of these results, we evaluated anti-lipid-peroxidative activity of HTHQ in three systems involving micelles, liposomes and rat liver microsomes. HTHQ exhibited a similar anti-oxidative activity to that of D,L-alpha-tocopherol against lipid peroxidation in linolate micelles initiated by addition of Fe2+. On the other hand, HTHQ exhibited approximately 4.8-fold higher anti-lipid-peroxidation activity than that of D,L-alpha-tocopherol against the peroxidation in phosphatidylcholine liposomes initiated by addition of Fe2+. Furthermore, HTHQ scavenged the lipid peroxides at a rate approximately 150 times higher than that of D,L-alpha-tocopherol against Fe3+ -ADP-induced lipid peroxidation in rat liver microsomes, indicating that the anti-lipid-peroxidation activity of HTHQ might be substantially elevated in biological systems in comparison with that of D,L-alpha-tocopherol. Based on these results, we suggest that HTHQ reacts directly with peroxyl radicals, such as t-butyl peroxyl radicals and peroxides of linolate micelles, liposomes and microsomes, by scavenging them to form stable free radicals. The resulting free radicals are presumed to be reduced by several reducing mechanisms in biological systems similarly to those of D,L-alpha-tocopherol, and then the lipid-peroxidation reactions will be terminated. In conclusion, HTHQ was found to be a potent anti-lipid-peroxidative compound and its antioxidation activity to be extremely elevated in biological systems, such as that of liver microsomes via the generation of stable free radicals. We propose that HTHQ is a potent anti-oxidative agent for use in future treatments for lipid-peroxide relevant diseases.

Animals↗
PubMed1997

The importance of sodium pyruvate in assessing damage produced by hydrogen peroxide.

Instability of hydrogen peroxide solutions was noted during the experimental exposure of human cells in culture to hydrogen peroxide in experiments designed to study the production and repair of DNA single-strand breaks. A hydrogen peroxide concentrate was diluted into culture medium, which was then added to experimental cell cultures at various times, with all cultures assessed for DNA damage at 2 h. Only cells treated by the first addition had observable DNA damage. This result was unexpected since these cells had had the maximum repair time. It was determined that the hydrogen peroxide had been eliminated by the culture medium. To determine the mechanism of this elimination, 200 microM hydrogen peroxide was added to various cell culture components, and the solutions were assayed for hydrogen peroxide after 1 h at 37 degrees C. Although most components (except the balanced salts) showed some hydrogen peroxide degradation, it was found that sodium pyruvate was most effective, by a wide margin, in eliminating hydrogen peroxide and its toxic effects. This was confirmed by addition of pyruvate to balanced salt solutions or buffers, and observing the same elimination of hydrogen peroxide. We subsequently found a few earlier reports describing the decarboxylation reaction between hydrogen peroxide and pyruvate, but no kinetic measurements have been published and there seems to be no general appreciation for the very high efficiency of this reaction. The present work presents a preliminary assessment of the importance of pyruvate in the study of hydrogen peroxide and other reactive oxygen species in mammalian cell culture.

Azides↗
PubMed1998

Effect of bile acids on lipid peroxidation: the role of iron.

The toxic effect of hydrophobic bile acids is claimed to be in part mediated by lipid peroxidation. Conversely, antioxidant properties of tauroursodeoxycholic acid (TUDC), a hydrophilic bile acid, have been suggested as a possible mechanism by which TUDC confers its beneficial effect in a variety of diseases. We have investigated the effect of taurodeoxycholic acid (TDC), a hydrophobic bile acid and TUDC on lipid peroxidation using a pure lipid system both in the presence and absence of iron ions. Neither TDC nor TUDC showed any effect on spontaneous lipid peroxidation of phosphatidylcholine liposomes or sodium arachidonate solution. This lack of effect excludes the possibility of direct prooxidant or antioxidant properties for TDC and TUDC. Addition of ferrous ions (0.1 mM) to the lipid system brought about a linear increase in lipid peroxidation with time. The presence of TDC caused an increase in the rate and extent of iron-stimulated lipid peroxidation. The propensity of bile acids to increase iron-induced lipid peroxidation was related to hydrophobicity of the individual bile acids, with the highest effect observed with taurolithocholic acid, whereas TUDC did not have any influence. The TDC-induced increase in the iron-stimulated lipid peroxidation was concentration dependent. Addition of TUDC (10 mM) completely abolished the effect of TDC (2 mM) on iron-induced lipid peroxidation. This finding suggests that TUDC does not function as an antioxidant per se but may prevent lipid peroxidation caused by TDC. In conclusion, only in the presence of iron ions, hydrophobic bile acids may enhance lipid peroxidation. TUDC has no antioxidant activity per se but may counter the TDC-induced increase in iron-stimulated lipid peroxidation.

Arachidonic Acid↗