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PubMed1989

Inhibitory effect of eugenol on Cu2+-catalyzed lipid peroxidation in human erythrocyte membranes.

1. The effects of eugenol on lipid peroxidation catalyzed by hydrogen peroxide (H2O2) or benzoyl peroxide (BPO) in the presence of copper ions were studied in human erythrocyte membranes. 2. The production of hydroxyl radicals was suggested in the peroxidation system catalyzed by H2O2/Cu2+. 3. H2O2/Cu2+-dependent peroxidation was inhibited by eugenol in a concentration-dependent manner; peroxidation was inhibited 62% by 200 microM eugenol. 4. In the presence of eugenol, the peroxidation catalyzed by BPO/Cu2+ was inhibited in a concentration-dependent manner, and more than 100 microM eugenol completely inhibited peroxidation. 5. The inhibitory effect of eugenol was non-competitive against Cu2+ in H2O2/Cu2+- and BPO/Cu2+-dependent peroxidation. 6. It is suggested that eugenol inhibits formation of hydroxyl radicals.

Benzoyl Peroxide↗

PubMed1992

Role of lipid peroxidation and antioxidants in aging process and thalassemia.

Oxygen free radicals and other oxygen derived species (Superoxide, O2-; Hydroperoxide, HOO; Singlet oxygen, 1O2-; Hydroxyl radical, OH; and Hydrogen peroxide, H2O2) including lipid peroxides have been suggested as important causative agents of aging and several human diseases, including cancer, multiple sclerosis, Parkinson's disease, autoimmune disease, ischemia, anemia, senile dementia, asbestosis and in thalassemia. This paper aims to communicate some of the theories and rationales in aging process and thalassemia.

Aging↗

PubMed1992

Mechanism of enhanced phagocytic response in protein a treated rat macrophages.

Protein A of S. aureus Cowan I has been shown to stimulate macrophage mediated phagocytosis. The present study was undertaken to understand the mechanism involved in the enhancement of phagocytosis of peritoneal macrophages by protein A. The lucigenin and luminol-dependent chemiluminescence (CL) of rat peritoneal macrophages, after incubation with various concentrations of protein A, flow-cytometric studies using DCFH-DA as a fluorescent compound and phagocytosis of sheep red blood cells (SRBCs) by rat peritoneal macrophages were studied. A significant increase in lucigenin dependent CL due to formation of superoxide anions (O2-.) and in luminol dependent CL due to formation of hydrogen peroxide (H2O2) was observed in protein A treated macrophages. A significant increase in intracellular hydrogen peroxide (H2O2) was also observed along with an increase in phagocytosis of SRBCs by protein A treated macrophages. The present findings indicate that protein A helps to increase phagocytosis and triggers respiratory burst of macrophages. Thus, both increased phagocytic response and respiratory burst of macrophages in protein A treated animals may be contributing to the antitumor property of protein A reported earlier.

Acridines↗

PubMed1989

Effects of hydrogen peroxide on action potentials and intracellular Ca2+ concentration of guinea pig heart.

Oxygen free radicals and Ca2+ overload have been implicated in the genesis of reperfusion induced arrhythmia and injury. Effects of hydrogen peroxide (H2O2) on action potentials and intracellular Ca2+ concentration ([Ca2+]i) were studied using guinea pig papillary muscles and ventricular myocytes. High concentration of H2O2 (10 mmol.litre-1) caused delayed afterdepolarisations in all six papillary muscles, and induced triggered activity in 3/6 preparations. Pretreatment with ryanodine (1 mumol.litre-1) abolished delayed afterdepolarisations and triggered activity induced by H2O2. [Ca2+]i and morphological changes in isolated ventricular myocytes of guinea pig were measured using fura-2. Quiescent and rod shaped myocytes became shortened and rounded (contracture) after the application of 0.1 and 1 mmol.litre-1 H2O2. [Ca2+]i increased from the control values of 53 (SEM 4) and 62(8) nmol.litre-1 to 110(29) and 105(24) nmol.litre-1 (p less than 0.05 v control) when cells were shortened during perfusion with 0.1 and 1 mmol.litre-1 H2O2, respectively. The values were 130(26) nmol.litre-1 (p less than 0.05 v control) and 100(18) nmol.litre-1 (p less than 0.05 v control) when the cells became rounded during perfusion with 0.1 and 1 mmol.litre-1 H2O2. We suggest that the arrhythmia caused by Ca2+ overload was induced by H2O2, possibly by lipid peroxidation of cell membrane. H2O2 was also shown to shorten cells and cause cell contracture (rounding). The mechanism of cell injury is not likely to be due to the Ca2+ overload, since the increase in [Ca2+]i during perfusion with H2O2 was not large.

Action Potentials↗

PubMed1991

Cytochrome c-catalyzed membrane lipid peroxidation by hydrogen peroxide.

Cytochrome c(3+)-catalyzed peroxidation of phosphatidylcholine liposomes by hydrogen peroxide (H2O2) was indicated by the production of thiobarbituric acid reactive substances, oxygen consumption, and emission of spontaneous chemiluminescence. The iron chelator diethylenetriaminepentaacetic acid (DTPA) only partially inhibited peroxidation when H2O2 concentrations were 200 microM or greater. In contrast, iron compounds such as ferric chloride, potassium ferricyanide, and hemin induced H2O2-dependent lipid peroxidation which was totally inhibitable by DTPA. Cyanide and urate, which react at or near the cytochrome-heme, completely prevented lipid peroxidation, while hydroxyl radical scavengers and superoxide dismutase had very little or no inhibitory effect. Changes in liposome surface charge did not influence cytochrome c3+ plus H2O2-dependent peroxidation, but a net negative charge was critical in favoring cytochrome c(3+)-dependent, H2O2-independent lipid auto-oxidative processes. These results show that reaction of cytochrome c with H2O2 promotes membrane oxidation by more than one chemical mechanism, including formation of high oxidation states of iron at the cytochrome-heme and also by heme iron release at higher H2O2 concentrations. Cytochrome c3+ could react with mitochondrial H2O2 to yield "site-specific" mitochondrial membrane lipid peroxidation during tissue oxidant stress.

Cytochrome c Group↗

PubMed1987

Superoxide removal and radiation protection in bacteria.

Previous work with procaryotic cells has identified one kind of lethal damage from ionizing radiation which occurs only within a specific range of low O2 concentrations, about 10(-6) to 10(-4) M. Within this range, protection can occur in three ways: through the enzymatic decomposition of hydrogen peroxide (H2O2) by added catalase, through the enzymatic degradation of superoxide anion radicals (.O2-) by added superoxide dismutase (SOD), and through scavenging hydroxyl radicals (.OH) by various additives. These results indicate that three radiolytic products, H2O2, .OH, and .O2- (and/or the conjugate acid, the perhydroxyl radical, .HO2) are involved in this single kind of radiation-induced damage. Although the radiolytic productions of H2O2 and .O2- are strongly enhanced in higher O2 concentrations, neither enzyme protects when these air-equilibrated bacteria are irradiated. These experiments address this apparent contradiction and focus on the specific issue of why the addition of SOD protects at low but not at high O2 concentrations. We propose that, at a given O2 concentration, .O2- (and/or .HO2) may either react (with some cellular component?) to cause damage or react (with itself) to form hydrogen peroxide (H2O2). The specific O2 concentration during irradiation would determine the relative rates of these competing reactions and therefore the O2 concentration itself would establish whether or not we will observe damage from .O2-.

Escherichia coli↗

PubMed1991

Hydrogen peroxide-induced renal injury. A protective role for pyruvate in vitro and in vivo.

Hydrogen peroxide (H2O2) contributes to renal cellular injury. alpha-Keto acids nonenzymatically reduce H2O2 to water while undergoing decarboxylation at the 1-carbon (1-C) position. We examined, in vitro and in vivo, the protective role of sodium pyruvate in H2O2-induced renal injury. Pyruvate effectively scavenged H2O2 in vitro, and suppressed H2O2-induced renal lipid peroxidation. Injury to LLC-PK1 cells induced by hydrogen peroxide was attenuated by pyruvate to an extent comparable to that seen with catalase. Studies utilizing [1-14C]pyruvate further demonstrated 1-C decarboxylation concurrent with cytoprotection by pyruvate from H2O2-induced injury. Pyruvate was also protective in vivo. Infusion of pyruvate before and during the intrarenal infusion of H2O2 attenuated H2O2-induced proteinuria. Systemic administration of pyruvate was also protective in the glycerol model of acute renal failure, a model also characterized by increased generation of H2O2. These findings indicate that pyruvate, a ubiquitous alpha-keto acid, scavenges H2O2 and protects renal tissue in vitro and in vivo from H2O2-mediated injury. These data suggest a potential therapeutic role for pyruvate in diseases in which increased generation of H2O2 is incriminated in renal damage.

Animals↗

PubMed1992

Reactions of copper(II)-N-polycarboxylate complexes with hydrogen peroxide in the presence of biological reductants: ESR evidence for the formation of hydroxyl radical.

The formation of hydroxyl radicals (.OH) by the reaction of CuII(edta) (edta: ethylenediaminetetraacetic acid) with hydrogen peroxide (H2O2) in the presence of biological reductants, such as L-ascorbic acid and L-cysteine, has been demonstrated for the first time by ESR spectroscopy using water-soluble spin-traps, 5,5-dimethyl-1-pyrroline N-oxide (DMPO, 1), alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN, 2) and 3,5-dibromo-4-nitrosobenzenesulfonate (DBNBS, 3). Ethylenediaminetetraacetic acid (edta) is one of the polyamine-N-polycarboxylate chelating agents and it is commonly used by chemists and biochemists. Edta can chelate several metal ions. It is known that the CuII(edta) complex is usually less active than free copper ions in radical reactions, whereas complexes of edta with Fe(II) or Fe(III) still react with hydrogen peroxide (H2O2) or superoxide ion (O2-) (1). In our previous papers (2-4), we also have shown that copper(II) complexes with polyamine-N-polycarboxylates, such as edta and dtpa (diethylenetriaminepentaacetic acid), do not react with H2O2, whereas CuII(en)2 (en: ethylenediamine) can easily do so to give hydroxyl radical (.OH) as a reactive intermediate. Further, we assumed that the change of redox potential of Cu(II) ions as a result of ligation with different ligands causes the difference in reactivity of Cu(II) complexes towards H2O2. To verify this assumption, the reactions of CuII(edta), which was chosen as a Cu(II)-polyamine-N-polycarboxylate complex, with H2O2 were investigated in the presence of some biological reductants, using an ESR-spin trapping method.(ABSTRACT TRUNCATED AT 250 WORDS)

Ascorbic Acid↗

PubMed1991

The antioxidant action of ergothioneine.

Ergothioneine is a product of plant origin that accumulates in animal tissues. Its suggested ability to act as an antioxidant has been evaluated. Ergothioneine is a powerful scavenger of hydroxyl radicals (.OH) and an inhibitor of iron or copper ion-dependent generation of .OH from hydrogen peroxide (H2O2). It is also an inhibitor of copper ion-dependent oxidation of oxyhaemoglobin, and of arachidonic acid peroxidation promoted by mixtures of myoglobin (or haemoglobin) and H2O2. Ergothioneine is a powerful scavenger of hypochlorous acid, being able to protect alpha 1-antiproteinase against inactivation by this molecule. By contrast, it does not react rapidly with superoxide (O2-) or hydrogen peroxide (H2O2) and it does not inhibit microsomal lipid peroxidation in the presence of iron ions. Overall, our results show that ergothioneine at the concentrations present in vivo could act as an antioxidant.

Animals↗

PubMed1991

Hydrogen peroxide-induced pulmonary vasodilation: role of guanosine 3',5'-cyclic monophosphate.

Hydrogen peroxide (H2O2), but not tertbutyl hydroperoxide, produces a concentration-dependent vasodilation of the pulmonary circulation in isolated saline perfused rabbit lungs when pulmonary arterial pressures (PAP) are raised with the thromboxane analogue U-46619. This vasodilation was enhanced in the presence of indomethacin, suggesting that H2O2 possesses both a prostaglandin-mediated constrictor and an additional dilator mechanism. In isolated rabbit intrapulmonary arteries the endothelium did not alter the dose-dependent relaxation of arterial rings to H2O2, and indomethacin enhanced the relaxant response of the peroxide. The decrease in PAP and relaxation of isolated pulmonary arteries observed with H2O2 was attenuated with 10 microM methylene blue, an inhibitor of soluble guanylate cyclase activation. M & B 22948, a guanosine 3',5'-cyclic monophosphate (cGMP)-selective phosphodiesterase inhibitor, enhanced the vasodilation or relaxation to the peroxide in both preparations. These changes were not endothelium dependent. Inhibition of the cGMP-associated endothelium-derived relaxant factor (EDRF) with nitro-L-arginine, did not alter relaxation of arterial rings to peroxide. Thus H2O2 appears to produce pulmonary vasodilation through the activation of guanylate cyclase and accumulation of cGMP. Both H2O2 and EDRF may function as tonic stimulators of guanylate cyclase in the pulmonary circulation and contribute to the maintenance of low basal pressures.

Animals↗

PubMed1992

Inducibility of the response of yeast cells to peroxide stress.

Exponential phase cells of the yeast, Saccharomyces cerevisiae when treated with a non-lethal concentration of hydrogen peroxide (H2O2; 0.2mM) for 60 min adapted to become resistant to the lethal effects of a higher dose of H2O2 (2mM). From studies using cycloheximide to inhibit protein synthesis it appears that protein synthesis is required for maximal induction of resistance but that some degree of protection from the lethal effects of peroxide can be acquired in the absence of protein synthesis. Treatment of cells with 50 micrograms cycloheximide ml-1 alone lead to them acquiring some protection from peroxide. Cells subjected to heat shock became more resistant to 2mM-H2O2; however, peroxide pretreatment did not confer thermotolerance. L-[35S]Methionine labelling of cells subjected to 0.2 mM-H2O2 stress showed that synthesis of at least ten polypeptides was induced by peroxide treatment. Some of these were also induced in cells subjected to heat shock (23 to 37 degrees C shift) but the synthesis of at least four polypeptides (45, 39.5, 38 and 24 kDa) was unique to peroxide-stressed cells. Resistance to peroxide was also inducible in an isogenic petite and an isogenic strain with a mutation in the HAP1 gene, indicating that the adaptive response does not require functional mitochondria.

Adaptation, Physiological↗

PubMed1987

Desferrioxamine as an electron donor. Inhibition of membranal lipid peroxidation initiated by H2O2-activated metmyoglobin and other peroxidizing systems.

Desferrioxamine (DFO) involvement in several peroxidative systems was studied. These systems included: a) membranal lipid peroxidation initiated by H2O2-activated metmyoglobin (or methemoglobin); b) phenol-red oxidation by activated metmyoglobin or horseradish peroxidase (HRP): c) beta-carotene-linoleate couple oxidation stimulated by lipoxygenase or hemin. Desferrioxamine was found to inhibit all these systems but not ferrioxamine (FO). Phenol-red oxidation by H2O2-horseradish peroxidase was inhibited competitively with DFO. Kinetic studies using the spectra changes in the Soret region of metmyoglobin suggest a mechanism by which H2O2 reacts with the iron-heme to form an intermediate of oxy-ferryl myoglobin that subsequently reacts with DFO to return the activated compound to the resting state. These activities of DFO resemble the reaction of other electron donors.

Cell Membrane↗

PubMed1989

Effects of culture duration on hydrogen peroxide-induced hepatocyte toxicity.

The effects of culture duration on primary cultured mouse hepatocyte antioxidant levels (superoxide dismutase, catalase, glutathione peroxidase, vitamin E, and glutathione) and susceptibility to glucose oxidase (GO)- and hydrogen peroxide (H2O2)-induced cell killing and lipid peroxidation were examined. Membrane fatty acid composition was also evaluated. Adult male B6C3F1/CrlBR mouse hepatocytes were isolated by collagenase perfusion of the liver and cultured on 60-mm plastic dishes in Leibovitz's L-15 medium supplemented with glucose (1 mg/ml), dexamethasone (1 microM), fetal bovine serum (10%, v/v), and gentamicin sulfate (50 micrograms/ml) for 0 hr (freshly isolated cells) to 96 hr. Hepatocyte toxicity (determined by lactate dehydrogenase release and lipid peroxidation) after a 2-hr exposure to GO (0.8-80 micrograms/ml) or H2O2 (1-5 mM) decreased with increased time in culture. This decreased hepatocyte sensitivity to GO and H2O2 toxicity was not related to antioxidant enzyme activity since superoxide dismutase, catalase, and glutathione peroxidase declined during the 96-hr culture period. In contrast, glutathione and vitamin E levels in the cultured hepatocytes rose to 274.9 +/- 8.3% and 220.6 +/- 18.6% of the levels in freshly isolated cells (129.6 +/- 11.5 nmol and 0.10 +/- 0.01 nmol per 10(6) hepatocytes, respectively). The percentage of polyunsaturated fatty acids in hepatocyte phospholipids and triglycerides decreased with culture duration while the percentage of oleic acid increased in esterified and free fatty acid pools after 2 hr in culture. Total fatty acids were not affected by time in culture. These results suggest that the decreased hepatocyte susceptibility to the toxic effects of hydrogen peroxide may have been due to elevations in cellular GSH and vitamin E levels and decreases in membrane polyunsaturated fatty acids. The data also indicate that hepatocytes in primary culture undergo changes in antioxidant levels and fatty acid composition that may affect free radical toxicity at different times in culture.

Animals↗

PubMed1989

Luteolytic actions of peroxide in rat ovarian cells.

A hallmark of luteolysis is leukocyte infiltration. Phagocytic leukocytes are well known to evoke a burst release of hydrogen peroxide (H2O2) of sufficient magnitude to injure cells. We, therefore, evaluated the effect of H2O2 in isolated rat luteal cells. Peroxide (100 microM; the near-half-maximal dose) markedly inhibited both LH-sensitive cAMP accumulation and progesterone production within 5 min of treatment. Cell levels of ATP were also reduced by H2O2, but not until 10 min after exposure, with more than 50% depletion within 60 min. This depletion of ATP by H2O2 was prevented by nicotinamide or 3-aminobenzamide, inhibitors of DNA repair, but these inhibitors did not prevent the antigonadotropic action of H2O2. cAMP accumulation in response to forskolin was not inhibited by H2O2 when ATP depletion was blocked with 3-aminobenzamide. The specific binding of radiolabeled hCG to isolated cells or the biological activity of LH was not affected by H2O2 pretreatment of the cells. Isobutylmethylxanthine had no effect on abrogation of LH-sensitive cAMP accumulation by H2O2. The actions of H2O2 were not mediated by prostaglandin, since indomethacin was without effect and an increase in prostaglandin F2 alpha production was not seen with H2O2 treatment. The acute luteolytic actions of H2O2 thus appear to be due to a very rapid desensitization of the LH-receptor complex, followed by depletion of ATP. The abrogation of luteotropic support and the injurious consequences of ATP depletion raise the possibility that H2O2 may be a physiological mediator of luteolysis.

1-Methyl-3-isobutylxanthine↗

PubMed1987

Oxidants and human disease: some new concepts.

Oxidant species such as superoxide radical (O.2-), hydrogen peroxide (H2O2), hydroxyl radical (HO.), and lipid peroxides (LOOH) are becoming increasingly implicated in human disease. However, the question of whether such oxidants are a major cause of tissue injury in human disease or are merely produced during such injury has been difficult to answer because of inadequate experimental techniques, and possibly because of an overemphasis on lipid peroxidation as a mechanism of oxidant injury. Recent developments in methodology, in our understanding of the primary mechanism of oxidant toxicity to cells, and in concepts of antioxidant protection are reviewed. Good evidence now exists for some role of oxidant damage to tissues in the pathology of several human diseases, including rheumatoid arthritis, reperfusion injury, immune injury to lung and kidney, and cerebral trauma or ischemia. These have led to promising suggestions for new therapeutic approaches.

Antioxidants↗

PubMed1985

Inhibition of neutrophil function by hydrogen peroxide. Effect of SH-group-containing compounds.

Stimulated neutrophils generate appreciable amounts of hydrogen peroxide (H2O2) which may be responsible for auto-oxidative injury and damage to adjacent cells. In the present study we describe inhibitory effects of H2O2 on neutrophil phagocytosis, bactericidal activity and associated metabolic processes as well as the effect of non-protein SH-compounds on H2O2-treated cells. Preincubation of neutrophils with low concentrations of H2O2 (1 mumoles/5 X 10(6) cell) results in delayed phagocytosis of Escherichia coli, which returns to normal levels in the later stages of incubation, while the activity of the HMPS and the production of O-2 and H2O2 remain unaffected. Bactericidal activity of the cells was more sensitive to peroxide treatment and even at low concentrations H2O2 induced some inhibition (12.2%) of neutrophils' capacity to kill E. coli. Increasing the concentrations of H2O2 in the preincubation mixtures resulted in a progressive decline in the neutrophils phagocytic and killing capacity for E. coli and was accompanied by inhibition of HMPS activity and the release of granule enzymes but not of O-2 or H2O2. The H2O2/O-2 molar ratio of peroxide-treated cells was elevated by up to 26.7% and this was followed closely by the reduction in the intracellular levels of reduced glutathione (GSH). Incubation of H2O2-treated neutrophils with all five SH-compounds used in the study resulted in the improvement of the phagocytic capacity of the cells. Improvement of the bactericidal capacity and degranulation responses of H2O2-treated neutrophils was achieved by incubation with cysteine, penicillamine, alpha-MPG and MMPC but not GSH. Stimulus-dependent H2O2 production by H2O2-treated cells, the H2O2/O-2 molar ratio and the intracellular levels of GSH remained unaltered after treatment with SH-compounds. The data shows that SH-compounds, in addition to their antiinflammatory properties, also have the ability to reverse the oxidant-induced inhibition of neutrophil function, a property of potential therapeutic significance.

Blood Bactericidal Activity↗

PubMed1991

Hydrogen peroxide-induced oxidative stress to the mammalian heart-muscle cell (cardiomyocyte): lethal peroxidative membrane injury.

Oxidative stress induced by hydrogen peroxide (H2O2) may contribute to the pathogenesis of ischemic-reperfusion injury in the heart. For the purpose of investigating directly the injury potential of H2O2 on heart muscle, a cellular model of H2O2-induced myocardial oxidative stress was developed. This model employed primary monolayer cultures of intact, beating neonatal-rat cardiomyocytes and discrete concentrations of reagent H2O2 in defined, supplement-free culture medium. Cardiomyocytes challenged with H2O2 readily metabolized it such that the culture content of H2O2 diminished over time, but was not depleted. The consequent H2O2-induced oxidative stress caused lethal sarcolemmal disruption (as measured by lactate dehydrogenase release), and cardiomyocyte integrity could be preserved by catalase. During oxidative stress, a spectrum of cellular derangements developed, including membrane phospholipid peroxidation, thiol oxidation, consumption of the major chain-breaking membrane antiperoxidant (alpha-tocopherol), and ATP loss. No net change in the protein or phospholipid contents of cardiomyocyte membranes accompanied H2O2-induced oxidative stress, but an increased turnover of these membrane constituents occurred in response to H2O2. Development of lethal cardiomyocyte injury during H2O2-induced oxidative stress did not require the presence of H2O2 itself; a brief "pulse" exposure of the cardiomyocytes to H2O2 was sufficient to incite the pathogenic mechanism leading to cell disruption. Cardiomyocyte disruption was dependent upon an intracellular source of redox-active iron and the iron-dependent transformation of internalized H2O2 into products (e.g., the hydroxyl radical) capable of initiating lipid peroxidation, since iron chelators and hydroxyl-radical scavengers were cytoprotective. The accelerated turnover of cardiomyocyte-membrane protein and phospholipid was inhibited by antiperoxidants, suggesting that the turnover reflected molecular repair of oxidized membrane constitutents. Likewise, the consumption of alpha-tocopherol and the oxidation of cellular thiols appeared to be epiphenomena of peroxidation. Antiperoxidant interventions coordinately abolished both H2O2-induced lipid peroxidation and sarcolemmal disruption, demonstrating that an intimate pathogenic relationship exists between sarcolemmal peroxidation and lethal compromise of cardiomyocyte integrity in response to H2O2-induced oxidative stress. Although sarcolemmal peroxidation was causally related to cardiomyocyte disruption during H2O2-induced oxidative stress, a nonperoxidative route of H2O2 cytotoxicity was also identified, which was expressed in the complete absence of cardiomyocyte-membrane peroxidation. The latter mode of H2O2-induced cardiomyocyte injury involved ATP loss such that membrane peroxidation and cardiomyocyte disruption on the one hand and cellular de-energization on the other could be completely dissociated.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗

PubMed1989

Pervanadate [peroxide(s) of vanadate] mimics insulin action in rat adipocytes via activation of the insulin receptor tyrosine kinase.

Both vanadate and hydrogen peroxide (H2O2) are known to have insulin-mimetic effects. We previously reported that the mixture of vanadate plus H2O2 results in the generation of a peroxide(s) of vanadate, which strongly enhances IGF-II binding to rat adipocytes (Kadota et al., 1987b). We now report that pervanadate mimics insulin in isolated rat adipocytes to (1) stimulate lipogenesis, (2) inhibit epinephrine-stimulated lipolysis, and (3) stimulate protein synthesis. The efficacy of pervanadate is comparable to that of insulin. However, it is 10(2)-10(3) times more potent than vanadate alone. Exposure of intact rat adipocytes to pervanadate was found to activate the WGA-purified insulin receptor tyrosine kinase assayed with the exogenous substrate poly(Glu80/Tyr20) in a dose-dependent manner to a maximum of 1464% of control at 10(-3) M compared with a maximum insulin effect of 1046% at 10(-6) M. In contrast, in vitro assayed autophosphorylation of the WGA-purified extract was increased 3-fold after exposure of intact cells to insulin but not significantly increased after pervanadate. Furthermore, high concentrations of pervanadate (10(-5) M) inhibited subsequent in vitro added insulin-stimulated autophosphorylation. In vitro addition of pervanadate to WGA-purified receptors could not stimulate autophosphorylation or exogenous tyrosine kinase activity and did not inhibit insulin-stimulated autophosphorylation. Labeling of intact adipocytes with [32P]orthophosphate followed by exposure to 10(-4) M pervanadate increased insulin receptor beta-subunit phosphorylation (7.9 +/- 3.0)-fold, while 10(-7) M insulin and 10(-4) vanadate increased labeling (5.3 +/- 1.8)- and (1.1 +/- 0.2)-fold, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗