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PubMed2004

Organic nitrites and NO: inhibition of lipid peroxidation and radical reactions.

Organic nitrites, such as i-amyl nitrite (IAN), are nitrovasodilator drugs used both clinically and recreationally. Nitrites are also chemically reasonable biological products of NO metabolism, in particular in both inhibition of lipid peroxidation by NO and induction of lipid peroxidation by peroxynitrite and NO2. Nitrites are also potential products of biomolecule nitrosation and intermediates in biotransformation of nitrate vasodilators. Although mechanisms can be drawn for both prooxidant and antioxidant activity, IAN has been observed to inhibit lipid peroxidation in a variety of systems. To test if the antioxidant activity of nitrites results from NO release alone, inhibition of lipid peroxidation was studied for four organic nitrites and four NO donor NONOates. Iron-induced lipid peroxidation in synaptosomal tissue homogenates and azo compound-initiated lipid peroxidation in liposomes and linoleic acid SDS comicelles were examined. Lipid peroxidation was quantified by TBARS and oxygen uptake analysis. A good correlation of rate of NO release with IC50 for inhibition of lipid peroxidation was observed for the NONOates, compatible with lipid radical chain termination by NO, for which a chain termination stoichiometry of 0.4-0.5 mol of lipid peroxyl radicals per mole of NO was determined. In neutral aqueous solution, nitrites also spontaneously released NO as measured by chemiluminescence; however, no correlation was observed between the rate constants of NO release for the nitrites and their inhibitor potency toward lipid peroxidation. Long chain nitrites were seen to be relatively good inhibitors of lipid peroxidation by mechanisms that must involve factors in addition to simple homolysis to release NO. Evidence for direct alpha-hydrogen atom abstraction from the nitrite by peroxyl radicals was obtained by analysis of aldehyde products and supported by MO calculations. The data suggest that lipid nitrites formed as NO chain termination products have the capacity to further inhibit lipid peroxidation and to release NO.

Animals↗
PubMed1996

Radical-initiated lipid peroxidation in low density lipoproteins: insights obtained from kinetic modeling.

We present kinetic models of various complexity for radical-initiated lipid peroxidation in low density lipoproteins (LDL). The models, comprised of simultaneous differential equations programmed in Mathematica, were used to evaluate the concentration profiles of the reactants of interest. Single-phase reaction schemes describing lipid peroxidation and antioxidation according to the "conventional" and tocopherol-mediated peroxidation (TMP) model were simulated for conditions of low and high radical fluxes produced by thermolabile azo initiators. The results show that the particular dependencies of the rates of lipid peroxidation (Rp) on the rates of initiation (Ri) for the two reaction schemes were accurately predicted by the simulations. Both models qualitatively predicted inhibition of lipid peroxidation in the presence of alpha-tocopherol (alpha-TOH) under high radical flux conditions, suggesting that both can describe inhibited lipid peroxidation in solution under these conditions. TMP, but not the conventional model, could also predict the experimentally observed complex behavior of LDL lipid peroxidation induced with different concentrations of azo initiators. Specifically, TMP faithfully reproduced the observed kinetic chain length of lipid peroxidation of > > 1 at low and < < 1 at high concentration of the initiator (i.e., 0.2 and 10 mM, respectively for LDL at 1 mumol apoB-100/L) during the alpha-TOH-containing period of oxidation. It also demonstrated the experimentally observed nondependence of RpTMP on Ri. Kinetic analysis of radical generation and initiation of lipid peroxidation in an extended, two-compartment model of TMP showed that phase separation of bimolecular reactions in a suspension of LDL particles can lead to a approximately 400-fold increase in the rate of lipid hydroperoxide formation. The experimentally observed co-antioxidant action of water-soluble ascorbate and lipid-soluble ubiquinol-10 were verified using this model. A simple biophysical model constituting the reactions of TMP and incorporating the compartmental nature of an LDL suspension is proposed. Together, the results demonstrate that TMP is the only model that fits the experimental data describing the early stages of LDL lipid peroxidation under various oxidizing conditions. The implications of our findings are discussed in relation to atherogenesis and a recently proposed alternative model of LDL lipid peroxidation (Abuja and Esterbauer (1995) Chem. Res. Toxicol. 8, 753).

Antioxidants↗
PubMed1998

Shigella dysenteriae type 1 toxin induced lipid peroxidation in enterocytes isolated from rabbit ileum.

To evaluate the role of reactive oxygen species (ROS) in Shigella dysenteriae 1 toxin (STx) mediated intestinal infection, the ligated rabbit small intestinal loops were injected with STx. The enterocytes isolated from STx treated rabbit ileal loops had a significantly higher level of lipid peroxidation as compared to enterocytes isolated from control rabbit ileum. To study the role of second messengers in STx mediated intestinal damage, the in vivo and in vitro effects of modulators of lipid peroxidation of enterocytes were used. The presence of Ca2+-ionophore A23187 enhanced the extent of lipid peroxidation in enterocytes isolated from the control and STx treated rabbit ileum. However, 1-verapamil only marginally decreased the lipid peroxidation level of enterocytes isolated from STx treated rabbit ileum. The in vitro effect of modulators was in agreement with in vivo studies. Dantrolene significantly decreased the extent of lipid peroxidation of enterocytes isolated from STx treated rabbit ileum. PMA significantly increased the lipid peroxidation level of enterocytes isolated from control ileum. However, PMA could not further enhance the lipid peroxidation level of enterocytes isolated from STx treated rabbit ileum. The presence of H-7 significantly decreased the extent of lipid peroxidation of enterocytes isolated from STx treated rabbit ileum. In vitro effect of PMA and H-7 was in agreement with that of in vivo findings. The role of arachidonic acid metabolites, prostaglandins (PGs), in mediating STx induced lipid peroxidation was also studied. The presence of indomethacin (a PG synthesis inhibitor) significantly decreased the lipid peroxidation induced by STx. These findings suggest that lipid peroxidation induced by STx is mediated through cytosolic calcium. The increase in (Ca2+)i leads to activation of PKC. A significant decrease in the enterocyte levels of antioxidant enzymes superoxide dismutase, catalase and reduced glutathione in STx treated rabbit ileum as compared to control was seen. A significant decrease in vitamin E levels was also observed. This suggests that there is decreased endogenous intestinal protection against ROS in STx mediated intestinal infection which could contribute to enterocyte membrane damage that ultimately leads to changes in membrane permeability and thus to fluid secretion.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2001

Lipid peroxidation in hepatic steatosis in humans is associated with hepatic fibrosis and occurs predominately in acinar zone 3.

BACKGROUND AND AIMS: Hepatic steatosis has been shown to be associated with lipid peroxidation and hepatic fibrosis in a variety of liver diseases including non-alcoholic fatty liver disease. However, the lobular distribution of lipid peroxidation associated with hepatic steatosis, and the influence of hepatic iron stores on this are unknown. The aim of this study was to assess the distribution of lipid peroxidation in association with these factors, and the relationship of this to the fibrogenic cascade. METHODS: Liver biopsies from 39 patients with varying degrees of hepatic steatosis were assessed for evidence of lipid peroxidation (malondialdehyde adducts), hepatic iron, inflammation, fibrosis, hepatic stellate cell activation (alpha-smooth muscle actin and TGF-beta expression) and collagen type I synthesis (procollagen alpha1 (I) mRNA). RESULTS: Lipid peroxidation occurred in and adjacent to fat-laden hepatocytes and was maximal in acinar zone 3. Fibrosis was associated with steatosis (P < 0.04), lipid peroxidation (P < 0.05) and hepatic iron stores (P < 0.02). Multivariate logistic regression analysis confirmed the association between steatosis and lipid peroxidation within zone 3 hepatocytes (P < 0.05), while for hepatic iron, lipid peroxidation was seen within sinusoidal cells (P < 0.05), particularly in zone 1 (P < 0.02). Steatosis was also associated with acinar inflammation (P < 0.005). alpha-Smooth muscle actin expression was present in association with both lipid peroxidation and fibrosis. Although the effects of steatosis and iron on lipid peroxidation and fibrosis were additive, there was no evidence of a specific synergistic interaction between them. CONCLUSIONS: These observations support a model where steatosis exerts an effect on fibrosis through lipid peroxidation, particularly in zone 3 hepatocytes.

Actins↗
PubMed1980

Studies of lipid peroxide formation in irradiated synthetic diets and the effects of storage after irradiation.

The effect of irradiation doses of gamma-rays or electrons within the range 100--2000 krad has been studied on lipid peroxide formation in artificial food mixtures containing lard, corn oil or herring oil mixed with starch, casein or other proteins. Lipid peroxide formation after irradiation was very low in lard: starch or corn oil: starch mixtures but very large concentrations of peroxide were formed in irradiated herring oil: starch mixtures. This was mainly a result of the occurrence of the highly unsaturated C20:4, C20:5 and C22:6 fatty acids in the herring oil which readily form lipid peroxide. Lipid peroxide formation immediately after irradiation was much lower after doses of electrons given at a high dose-rate than after similar doses of gamma-rays given at low dose-rates but it increased rapidly in the samples irradiated with electrons during the period immediately following irradiation. Lipid peroxide formation changed rapidly during post-irradiation storage and was dependent on the type of radiation, the dose, the dose-rate, the time after irradiation and the temperatures of the post-irradiation storage. The concentration of peroxide in mixtures irradiated with gamma-rays formed after 2--3 days post-irradiation storage was dose-rate dependent and much greater after irradiation with gamma-rays given at a very low dose-rate than with gamma-rays given at a high dose-rate. Lipid peroxide increased after irradiation much more rapidly at 37 degrees C than at 4 degrees C or 21 degrees C but all irradiated samples a maximum concentration of peroxide was eventually formed, the time delay being temperature dependent. After reaching a maximum, the concentrations of both hydroperoxides and aledhyde breakdown products in all irradiated samples steadily fell to relatively low values. Peroxide yields were greater if the fat was dispersed in an inert medium such as starch than when irradiated in the pure form and were also dependent on the presence of water in the dispersant medium. Proteins such as casein or ovalbumin inhibited lipid peroxide formation in unsaturated fats.

Animal Feed↗
PubMed1985

Interaction of lipid peroxidation and calcium in the pathogenesis of neuronal injury.

The interactions between lipid peroxidation and calcium in mediating damage to central nervous system membranes have been examined in several in vitro systems. Using isolated rat brain synaptosomes, brain mitochondria, or cultured fetal mouse spinal cord neurons, Ca2+ was found to markedly enhance lipid peroxidation-induced disruption of membrane function. Gamma-aminobutyric acid (GABA) uptake by synaptosomes was inhibited 25% by either lipid peroxidation (induced with xanthine and xanthine oxidase) or Ca2+ alone, whereas inhibition was 46% with their combination. Ca2+ enhancement of lipid peroxidation-induced damage to synaptosomes was intensified by the Ca2+ ionophore, A23187, and was partially blocked by the Ca2+ channel blocker, verapamil. Similarly, inhibition of state 3 respiration in isolated rat brain mitochondria was observed with Ca2+ and a free radical generating system (xanthine and xanthine oxidase) under conditions where either insult alone failed to cause detectable damage. Na+,K+-ATPase activity of cultured fetal mouse spinal cord neurons was inhibited 32% when cells were incubated for 30 minutes in the presence of both A23187 and a free radical generating system. However, Na+,K+-ATPase was not affected during a 30 minute incubation with either A23187 or radical generating system alone. In further studies, peroxidation of rat brain synaptosomes by ferrous iron (Fe2+) and H2O2 was coupled with a rapid and large (2-7-fold) uptake of Ca2+ by synaptosomes. Fe2+ also enhanced Ca2+ uptake by spinal cord neurons in culture, an effect that was coincident with peroxidation of neuronal membranes and the release of arachidonic acid from cells. Iron-induced Ca2+ uptake was blocked by high concentrations of either desferrioxamine or methylprednisolone, whereas Ca2+ channel blockers did not affect Ca2+ uptake induced by Fe2+. Finally, peroxidation of membrane lipids by Fe2+ was stimulated by Ca2+. Concentrations of Ca2+ as low as 10(-9) M increased peroxidation reactions within brain synaptosomal membranes. The results of these studies indicate that lipid peroxidation and Ca2+ can synergistically act to damage biologic membranes. The findings suggest that Ca2+ and lipid peroxidation cannot be considered as separate entities in the pathophysiology of CNS trauma. A hypothesis proposing an inseparable interplay between lipid peroxidation and Ca2+ in the pathogenesis of traumatic and ischemic cell injury is presented.

Animals↗
PubMed1996

Synergistic renal protection by combining alkaline-diuresis with lipid peroxidation inhibitors in rhabdomyolysis: possible interaction between oxidant and non-oxidant mechanisms.

BACKGROUND AND PURPOSE: Heme-proteins, besides causing renal tubular obstruction, may contribute to rhabdomyolysis-induced renal injury through a heme-iron-mediated lipid peroxidation process. In the present study, we compared the combined therapy of a lipid peroxidation inhibitor, 21-aminosteroid (21-AS) and fluid-alkaline-mannitol (FAM) diuresis with either of them alone to determine the efficacy of the combination therapy and to delineate the roles of lipid peroxidation and cast formation. METHODS AND RESULTS: Employing Raman spectroscopy, we confirmed in vitro the ability of 21-AS to inhibit iron-induced fatty acid peroxidation. 21-AS was then administered to rats developing renal failure from glycerol-induced rhabdomyolysis. Although 21-AS inhibited rhabdomyolysis-induced plasma and renal lipid peroxidation, renal protection was incomplete. Administration of FAM to inhibit cast formation afforded a better renal protection. However, when these therapies were combined to inhibit both lipid peroxidation and cast formation, there was a synergistic renal functional protection. This was accompanied by a maximum inhibition of renal and plasma lipid peroxidation, as well as, renal tubular necrosis and cast formation. Compared to combination therapy, FAM therapy alone, despite identical volume, was accompanied by a higher tubular necrosis and cast formation. CONCLUSIONS: That combining a lipid peroxidation inhibitor with fluid-alkaline diuresis in rhabdomyolysis further lowers renal lipid peroxidation, tubular necrosis and cast formation and synergistically limits renal dysfunction (i) supports a role for lipid peroxidation in the pathophysiology of rhabdomyolysis ARF, (ii) underscores the role of the intratubular heme retention, a cause for tubular obstruction as well as a source for prodigious amount of iron, likely involved in the lipid peroxidation, and (iii) raises the possibility of interactions between non-oxidant and oxidant mechanisms.

Acute Kidney Injury↗
PubMed2004

Efficiency of benzoyl peroxide-erythromycin gel in comparison with metronidazole gel in the treatment of acne rosacea.

Oral wide-spectrum antibiotics are the linchpin of rosacea treatment. Oral and topical metronidazole, topical tretinoin, and topical benzoyl peroxide may also be used in the treatment of rosacea. We aimed to show that benzoyl peroxide-erythromycin gel is efficient in the treatment of acne rosacea. Fifty-six patients with acne rosacea were enrolled in our study. We administered benzoyl peroxide-erythromycin gel to 27 patients and metronidazole gel to 29 patients. In all the patients, the intensities of erythema, telangiectasia, papules/pustules, and nodules were evaluated before, during and after the treatment. The positivity of Demodex folliculorum from skin scratches was compared between the two groups at each visit. At the end of the therapy on the third examination, in the benzoyl peroxide-erythromycin group, 91.7% of the patients showed marked clinical improvement, and 8.3% of them showed complete remission. In the metronidazole group, 73.3% showed marked clinical improvement, and 26.7% of them showed complete remission. Clinical improvement in the papular component was 65.2% for the benzoyl peroxide-erythromycin group, and 81.5% for metronidazole group. In the first examination, the clinical results of the agents were similar. Although both of the drugs were found to be effective in the second and third examinations, metronidazole gel was more effective than benzoyl peroxide-erythromycin. Both of the drugs were found to be significantly effective especially in treating the papular component of rosacea. Demodex folliculorum was found to be positive in 74.1% of the benzoyl peroxide-erythromycin group and in 62.1% of the metronidazole group at the beginning. In the benzoyl peroxide-erythromycin group, 40.7% of Demodex folliculorum positive patients, became negative by the first examination. This was 17.2% for the metronidazole group. In the benzoyl peroxide-erythromycin group, among the patients who were positive for Demodex folliculorum in the first examination, 37.5% of them became negative. This was 36.7% for the metronidazole group. Benzoyl peroxide-erythromycin gel was superior to metronidazole gel in decreasing Demodex folliculorum by the first examination, but the effect of the two drugs on Demodex folliculorum was similar by the second examination. As a result, topically applied combined benzoyl peroxide-erythromycin gel may be an alternative choice of treatment for acne rosacea.

Administration, Cutaneous↗
PubMedDate not supplied

Lipid peroxidation and glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase, and glucose-6-phosphate dehydrogenase activities in FeCl3-induced epileptogenic foci in the rat brain.

This study investigated the relationship between lipid peroxidation, subsequent activation of antioxidative enzymes, and development of iron-induced epilepsy in the rat. Epileptic foci were produced in rat cerebral cortex by intracortical injection of ferric chloride (FeCl3). The epileptic foci were identified by electrocorticography (ECoG). Epileptiform ECoG activity was shown to occur in the contralateral homotopic cerebral cortex as well. We measured levels of lipid peroxides and changes in the activities of the enzymes: superoxide dismutase (SOD), glutathione peroxidase (GP), glutathione reductase (GR), catalase (CA), and glucose-6-phosphate dehydrogenase (G6P) in the epileptogenic focus (both ipsilateral and contralateral) at days 3, 8, 15, and 23 after FeCl3 injection. Biochemical estimations were made in subcellular fractions, and changes in the ipsilateral site were compared with those in the contralateral site. The results of this study showed that large increases in lipid peroxidation were associated with development and buildup of the ECoG epileptiform discharges. Lipid peroxides increased in the ipsilateral focus by approximately 100% as compared with control. In the contralateral site, however, the increase in lipid peroxides was marginal only. The increase in lipid peroxidation was concomitant with development of the high level of epileptiform activity. The time course of changes in lipid peroxidation paralleled the time course of development and persistence of the epileptiform activity. Regarding changes in the enzyme activities accompanying development of iron epilepsy, the data showed that although SOD and G6P increased by approximately 60% and GR increased by approximately 40%, the increases in the enzyme GP and CA were much lower, less than 20%. Thus, comparatively less increase in CA and GP activities produces a deficiency of these two enzymes in the iron (ipsilateral) focus. Among the various biochemical disturbances that have been identified as involved in epileptogenesis, peroxidative injury resulting from lipid peroxidation in neural plasma membrane may be causally related to development of paroxysmal epileptiform activity in the iron focus. Since GP is an enzyme of major importance in detoxification of lipid peroxides in the brain, based on the results presented in this article, it appears reasonable to suggest that GP deficiency causes lipid peroxidation to increase tremendously during iron epileptogenesis.

Animals↗
PubMed2006

The ability of thiourea to scavenge hydrogen peroxide and hydroxyl radicals during the intra-coronal bleaching of bloodstained root-filled teeth.

BACKGROUND: Hydrogen peroxide, an agent used in the intra-coronal bleaching of root-filled teeth for over a century, has been shown to diffuse from the pulp chamber to the outer root surface. Furthermore, it has been demonstrated that destructive hydroxyl radicals, the by-products of the bleaching process, have been detected on the external root surface. The control of such diffusion may be of importance in minimizing the risk of invasive cervical resorption (ICR) which has been linked to intra-coronal bleaching of discoloured root-filled teeth using hydrogen peroxide. The aims of the present in vitro study are to quantify the diffusion of hydrogen peroxide and hydroxyl radicals to the outer root surface following intra-coronal bleaching, and to evaluate the ability of thiourea incorporated into the bleaching protocol to scavenge residual hydrogen peroxide and hydroxyl radicals. METHODS: Thirty-five single rooted premolar teeth with intact cementum at the cemento-enamel junction were used in this project. Thirty teeth were stained with red blood cells and root-filled with gutta-percha and AH26. The five unstained teeth were root-filled and constituted a negative control (Group 1). The stained teeth were divided equally into the following experimental groups and subjected to various intra-coronal bleaching regimes: Group 2--'walking bleach' with 20 microl 30 per cent w/w hydrogen peroxide; Group 3--20 microl 30 per cent w/w hydrogen peroxide and thermocatalytically activated; Group 4--20 microl acidified thiourea; Group 5--20 microl acidified thiourea and 20 microl 30 per cent w/w hydrogen peroxide; Group 6--20 microl acidified thiourea and 20 microl one per cent sodium hypochlorite; Group 7--20 microl acidified thiourea, 20 microl one per cent sodium hypochlorite and 20 microl 30 per cent w/w hydrogen peroxide. The reaction products of the bleaching process were quantified at the outer root surface using high performance liquid chromatography and electrochemical detection (HPLC-ECD). RESULTS: Results showed that hydrogen peroxide used alone in Groups 2 and 3 was able to be detected at the outer root surface in 100 per cent of the samples, and that the presence of the hydroxyl radical generated in both groups was detected in equal amounts (P < 0.05). When thiourea was incorporated into the bleaching protocols in Groups 5-7, it was shown to scavenge both hydrogen peroxide and hydroxyl radicals to a significant degree (P < 0.05). CONCLUSIONS: Acidulated thiourea is an effective scavenger of residual hydrogen peroxide and hydroxyl radicals generated during the intra-coronal bleaching of bloodstained root-filled teeth.

Antioxidants↗
PubMed1986

Rat lung microsomal lipid peroxidation: effects of vitamin E and reduced glutathione.

Lung microsomal membranes that contain the redox active components associated with the mixed-function oxidase system can be peroxidized in vitro. To investigate the characteristics of rat lung microsomal lipid peroxidation, we performed experiments using a variety of peroxidation initiators and microsomes obtained from normal and vitamin E-deficient rats. We found that lung microsomes obtained from normal rats are peroxidized much less than liver microsomes obtained from the same animals. Only initiation systems using very high concentrations of ferrous iron produced any significant peroxidation of normal rat lung microsomes. Lung microsomes obtained from vitamin E-deficient rats were found to be much more susceptible to peroxidation. Glutathione (GSH) was effective in inhibiting peroxidation when lung microsomes from normal rats were peroxidized. GSH was not effective in decreasing peroxidation when microsomes from vitamin E-deficient rats were peroxidized in the same system. We conclude that both GSH and vitamin E protect lung microsomal membranes from peroxidation. Glutathione protection appears to be related to the presence of a sulfhydryl group.

Animals↗
PubMed1990

Modulation of inflammatory cell function by cotton bract tannin: changes in the capacity of alveolar macrophages and neutrophils to produce hydrogen peroxide.

Inhalation of cotton mill dust leads to the development of the occupational lung disease byssinosis in a portion of the exposed workers. Condensed tannins present in the dust have biologic activities consistent with the hypothesis that they are one of the etiologic agents for the disease. Inhalation of either cotton dust or tannin provokes an acute inflammatory response characterized by the influx of neutrophils into the airways. The secretion of a low-molecular-weight, lipid neutrophil chemotactic factor from the alveolar macrophages in response to tannin stimulation appears to be important in this inflammatory process. In these studies, the effect of tannin the ability of alveolar macrophages and neutrophils to produce hydrogen peroxide was examined. Low concentrations of tannin itself induced a modest production of hydrogen peroxide from conditioned rabbit alveolar macrophages, while higher concentrations failed to induce peroxide production. In the presence of an independent stimulator of peroxide production (concanavalin A), tannin inhibited peroxide production at all concentrations examined. Aqueous extracts of cotton mill dust (CDE) had an identical effect on peroxide production in a manner that indicated that the tannin present in the dust was responsible for the effect. Like its direct effect on macrophage peroxide production, tannin induced modest peroxide production in human neutrophils. However, unlike its effect on macrophages, tannin enhanced the peroxide production induced by the presence of an independent stimulator (phorbol myristate acetate). CDE had a similar effect on peroxide production, but the dose-response curves suggested that only the high-molecular-weight polymers of tannin present in the CDE were able to enhance peroxide production.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Evidence that hydrogen peroxide blocks hormone-sensitive cholesterol transport into mitochondria of rat luteal cells.

In luteal and granulosa cells, hydrogen peroxide abruptly inhibits activation of adenylate cyclase by receptor-bound gonadotropin and blocks steroidogenesis. In the present studies a post-cAMP site of peroxide action on inhibition of steroidogenesis was investigated. Steroidogenesis, stimulated by dibutyryl or 8-bromo-cAMP, was inhibited by hydrogen peroxide. Yet, cAMP-dependent protein kinase activation in cytosol or intact cells was unaffected by peroxide treatment. Hydrogen peroxide also did not inhibit the activity of cholesterol esterase and acyl coenzyme-A:acyltransferase. Progesterone synthesis was maximally increased 5- to 50-fold with 25- and 22-hydroxycholesterol, respectively. Unlike that seen with cAMP analogs and LH, however, progestin synthesis stimulated by these cell- and mitochondria-permeant cholesterol analogs was not inhibited by hydrogen peroxide. Treatment of animals with amino-glutethimide produces a marked accumulation of steroidogenic cholesterol substrate and a large increase in hormone-independent steroidogenesis in subsequently isolated and washed luteal tissue. In this paradigm, hydrogen peroxide did not inhibit elevated basal progesterone synthesis in luteal cells produced by in vivo aminoglutethimide treatment, yet LH-stimulated steroidogenesis was blocked. However, treatment of luteal cells with hydrogen peroxide inhibited pregnenolone synthesis in isolated mitochondria, an effect partially reversed by the addition of luteal cell cytosol. In summary, while peroxide inhibited cAMP-dependent steroidogenesis, it did not appear to inhibit protein kinase activation or mobilization of cholesterol from intracellular esterified stores. Although peroxide inhibited pregnenolone synthesis, it had no effect on steroidogenesis when substrate was made available by either addition of cholesterol analogs or prior treatment with aminoglutethimide in vivo. We conclude, therefore, that hydrogen peroxide inhibits steroidogenesis by blocking intracellular transport of cholesterol to mitochondria or translocation of cholesterol across the outer mitochondrial membrane.

Animals↗
PubMed1984

Effect of alpha-tocopherol on lipid peroxidation and acyl chain mobility of liver microsomes from vitamin E-difficient rat.

Effects of alpha-tocopherol on lipid peroxidation and membrane fluidity were studied in liver microsomes from vitamin E (alpha-tocopherol)-deficient rats using NADPH as a substrate. Microsomes containing various contents of alpha-tocopherol were prepared by incubation with various concentrations of alpha-tocopherol in ethanol solution. NADPH-dependent lipid peroxidation decreased the content of polyunsaturated fatty acids, arachidonic acid and 4, 7, 10, 13, 16, 19-docosahexaenoic acid. The treatment with alpha-tocopherol before peroxidation reduced the production of lipid peroxides and the change in fatty acid composition even at the lowest content of alpha-tocopherol dealt with in this experiment, 0.2 molar fraction, while addition of alpha-tocopherol after peroxidation resulted in a slight inhibition of peroxide production and small alteration in fatty acid composition. By an ESR measurement using stearate spin probe, the alpha-tocopherol incorporated into microsomes did not alter the acyl chain mobility up to 0.2 molar fraction but reduced the mobility above 0.2 molar fraction. The acyl chain mobility was markedly decreased by lipid peroxidation. The decrease of membrane fluidity was repressed in microsomes treated with alpha-tocopherol before peroxidation, but was not repressed in microsomes treated after peroxidation. The experiment using artificial membranes of egg yolk phosphatidylcholine and rat liver phosphatidylcholine revealed that the effect of alpha-tocopherol on membrane fluidity depends on the fatty acid composition of phospholipid, especially the content of arachidonic acid. On the other hand, the mobility of the fatty acyl chain was not affected by spermine at concentrations which could inhibit lipid peroxidation. These results suggest that the inhibitory effect of alpha-tocopherol on lipid peroxidation is due to antioxidant activity rather than the indirect effect of membrane stabilization.

Acylation↗
PubMedDate not supplied

Metabolism of 3-tert-butyl-4-hydroxyanisole by horseradish peroxidase and hydrogen peroxide.

3-Tert-butyl-4-hydroxyanisole (3-BHA) was metabolized in the presence of horseradish peroxidase and hydrogen peroxide to 2-tert-butyl-p-benzoquinone (TBQ), 2,3-epoxy-5-tert-butyl-1,4-benzoquinone (TBQ-epoxide), and two known dimers. The formation of TBQ from 3-BHA required both horseradish peroxidase and hydrogen peroxide. When 2.5 mM 3-BHA was incubated with horseradish peroxidase and hydrogen peroxide, the formation of TBQ increased with hydrogen peroxide concentration up to 5 mM and decreased gradually at higher concentrations of hydrogen peroxide. On the other hand, the formation of TBQ-epoxide from 3-BHA increased, depending on hydrogen peroxide concentration at higher concentrations than 1 mM. In incubating 2-tert-butylhydroquinone (TBHQ) with horseradish peroxidase and hydrogen peroxide, TBHQ was rapidly oxidized to TBQ, and then TBQ-epoxide was also produced at concentrations more than 2.5 mM of hydrogen peroxide. In the absence of horseradish peroxidase, the incubation of TBQ with hydrogen peroxide resulted in TBQ-epoxide production. These results suggest that 3-BHA is metabolized to TBHQ, which is rapidly oxidized to TBQ, by horseradish peroxidase and hydrogen peroxide, and then TBQ is converted to TBQ-epoxide by only hydrogen peroxide.

Butylated Hydroxyanisole↗
PubMed2006

[The hydrogen peroxide paradox].

Since the discovery of hydrogen peroxide in 1819 it was known as a toxic agent for human organs. Due to the recent findings its role should be reevaluated. This review discusses the toxic and physiological roles of hydrogen peroxide and functions of enzyme catalase which is the main regulator of hydrogen peroxide metabolism. The concentration of hydrogen peroxide changes between 0,05 micromol/l and 117 micromol/l in exhaled breath condensate and in human fluids. Hydrogen peroxide is generated by physiological processes such as glycation, phagocytosis, cell metabolism and by pathological changes such as different tumors and side effects of some drugs. The main regulator of toxic concentration of hydrogen peroxide is the enzyme catalase while glutathione peroxidase and hemoglobin has a limited role in this process. Low concentration of hydrogen peroxide plays a role in degradation of some proteins, as a messenger in cell signaling and could contribute to apoptosis. The enzyme catalase, due to its structure and function, is very effective in destroying the toxic concentration of hydrogen peroxide without changing its low, physiologic concentration. Decrease in catalase due to anemia, decreased synthesis and especially to its inherited deficiency may be a risk factor in diabetes, cell damage due to ischemia, in uricase and ascorbic acid treatment as well as in sterilization with hydrogen peroxide. The hydrogen peroxide paradox means that its low concentration is vital for some physiological processes while its high concentration is toxic for human cells. The main regulator of hydrogen peroxide concentration is the enzyme catalase and its deficiency may be a risk factor for some pathological changes.

Animals↗
PubMed1975

The formation of hydrogen peroxide during the oxidation of reduced nicotinamide adenine dinucleotide by cytochrome o from Vitreoscilla.

The formation of hydrogen peroxide during the oxidation of NADH by purified preparations of cytochrome o has been demonstrated by employing three independent methods: polarographic, colorimetric, and fluorometric. The first two methods were used to assay for the accumulation of hydrogen peroxide and showed that hydrogen peroxide did accumulate as a product, but only about 30% of the oxygen consumed or 15 to 20% of the NADH oxidized was recoverable as hydrogen peroxide. This lack of 1:1 stoichiometry was not due to residual catalase activity in these preparations which could be eliminated by freeze-thawing. Thus, hydrogen peroxide may not be the sole or primary product of the NADH-cytochrome o oxidase reaction. The fluorometric assay could be coupled directly to the NADH-cytochrome o oxidase reaction in one medium, and this method showed that hydrogen peroxide was generated continuously from the beginning of the reaction in a 1:1 stoichiometry, hydrogen peroxide generated to NADH oxidized. This result suggests that hydrogen peroxide is an intermediate that can be trapped efficiently under the conditions of the fluorometric assay, whereas under the conditions of the first two assays most of the hydrogen peroxide generated undergoes further reaction. Exogenously added FAD or FMN increased the percentage of hydrogen peroxide that accumulated in the NADHcytochrome o oxidase reaction. Flavin is believed to act on the reductase side of cytochrome o so the increased percentage of hydrogen peroxide is not likely to result from the direct reaction of reduced flavin with oxygen.

Bacteria↗
PubMed1981

Superoxide dependent lipid peroxidation.

Rat liver microsomal NADPH-dependent lipid peroxidation and xanthine oxidase-promoted lipid peroxidation were reviewed and compared to see if a unified mechanism is involved in each system. These systems were also compared to hydroxyl radical-dependent lipid peroxidation in order to determine the physiological significance of the different mechanisms of lipid peroxidation. Fenton's reagent very readily promotes lipid peroxidation, which is inhibited by catalase and hydroxyl radical traps but not by superoxide dismutase. However, the addition of ADP to Fenton's reagent results in a type of lipid peroxidation that is not inhibited by hydroxyl radical traps and the amount of hydroxyl radical spin trap adducts formed is much less. Xanthine oxidase-promoted lipid peroxidation is not inhibited by catalase and is greatly stimulated by ADP. Microsomal NADPH-dependent lipid peroxidation is also dramatically stimulated by ADP in Tris buffer but not in phosphate buffer. Hydroxyl radical traps are without effect in both microsomes and xanthine oxidase-promoted lipid peroxidation. These results suggest several in vitro mechanisms for the initiation of lipid peroxidation but do not support the hydroxyl radical for a role in physiological lipid peroxidation.

Animals↗