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PubMed1992

[Formation and removal of active oxygen species and lipid peroxides in biological systems].

The mechanisms of formation and removal of active oxygen species and lipid peroxides in biological systems have been briefly reviewed. Cytotoxic active oxygen species can be classified into two types: (a) radical species such as O2-. (superoxide) and HO. (hydroxyl radical) and (b) non-radical species such as H2O2 (hydrogen peroxide) and 1O2 (singlet oxygen). The direct or indirect attack of active oxygen species on polyunsaturated fatty acids, essential constituents of biological membranes, has been shown to result in the formation of a number of peroxidative lipid breakdown-products: LOOH (lipid hydroperoxide), LOO. (lipid peroxyl radical) and LO. (lipid alkoxyl radical). The lipid peroxide decomposition is probably dependent on the presence of ferric-ferrous ions. These processes are called lipid peroxidation reactions. In recent years, there has been a renewed interest in the role played by lipid peroxidation in many disease states. The multiple lines of defense against toxic oxygen intermediates consist of enzymatic systems, glutathione peroxidase, catalase and superoxide dismutase, and furthermore involves antioxidant capacities such as those of vitamin E and vitamin C. In biological systems, there are naturally occurring lipid-soluble (vitamin E and ubiquinone) and water-soluble (vitamin C, reduced glutathione and uric acid) antioxidants. Therefore, so long as homeostasis is maintained between the rate of radical generation and the rate of radical dissipation, the cellular generation of radicals may not be harmful. In contrast, this balance can be disturbed if cellular defenses are decreased or if there is a significant increase in the flux of radical generation. Once lipid peroxidation is initiated, the reactive intermediate formed induces cell damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Lipid peroxidation and generations of oxygen radicals induced by cephaloridine in renal cortical microsomes of rats.

To investigate whether oxygen radicals would be generated by cephaloridine (CER) in the renal cortical microsomes obtained from rats and whether the microsomal lipid peroxidation would be promoted by CER, the microsomes were incubated under a pure oxygen atmosphere in a medium containing the reduced nicotinamide adenine dinucleotide phosphate regenerating system, under various conditions. Generations of superoxide anion and hydrogen peroxide and malondialdehyde formation were all dependent on microsomal protein concentrations, incubation periods and CER concentrations. Scavengers of the microsomal lipid peroxidation induced by CER, (+)-cyanidanol-3, mannitol, sodium benzoate and N-acetyl tryptophan, which are scavengers of hydroxyl free radicals, inhibited the CER-stimulated lipid peroxidation in the microsomes. Histidine, a scavenger of hydroxyl free radicals and singlet oxygen, and alpha-tocopherol, reduced-glutathione and NN'-diphenyl-p-phenylenediamine, the three of which are non-specific antioxidants, also inhibited the CER-stimulated lipid peroxidation in the microsomes. Accordingly, our findings may strongly support that CER generates not only superoxide anions and hydrogen peroxide but also hydroxyl free radicals in the kidney, and these generated oxygen radicals react with the membrane lipids to induce peroxidation and nephrotoxicity.

Animals↗
PubMed1989

Sub-chronic effects of styrene and styrene oxide on lipid peroxidation and the metabolism of glutathione in rat liver and brain.

Sub-chronic effects of styrene and styrene oxide on lipid peroxidation, glutathione contents and glutathione reductase activities in the liver and brain were examined after intraperitoneal administration to rats 3 times a week for 7 weeks. Styrene (300, 400 and 500 mg/kg) and styrene oxide (200 and 300 mg/kg) increased lipid peroxidation in the liver after 7 weeks of treatment. Hepatic lipid peroxidation in the rats treated with a higher dose of styrene oxide (400 mg/kg) was significantly enhanced even after 2 weeks of treatment. On the other hand, no change in lipid peroxidation was observed in the brain under the above conditions. Neither glutathione contents nor glutathione reductase activities in the liver and brain were altered at 40 h after the last of these sub-chronic treatments. To elucidate the cause of lipid peroxidation, the time courses of glutathione content after treatment with either styrene or styrene oxide (300 mg/kg) were studied in more detail. Significant decreases in both the GSH and GSSG contents were detected shortly after these treatments and the levels recovered to the control values at 40 h in these organs, although the changes were less significant in the brain of rats treated with styrene. These results suggest that enhancement of lipid peroxidation in the liver after treatment with styrene or styrene oxide was a consequence of repeated depletions of glutathione to certain critical levels and delayed recovery of lipid peroxides.

Animals↗
PubMed1985

Effect of ascorbate on red blood cell lipid peroxidation.

The present study investigates the effect of ascorbate on red cell lipid peroxidation. At a concentration between 0.2 mmol - 20 mmol/1 ascorbic acid reduces hydrogen peroxide-induced red blood cell lipid peroxidation resulting in a marked decrease in ethane and pentane production as well as in haemolysis. Ascorbic acid also shows an antioxidant effect on chelated iron-catalyzed hydrogen peroxide-induced peroxidation of erythrocyte membranes. At a concentration of 10 mmol/1 ascorbic acid totally inhibits oxidative break-down of polyunsaturated fatty acids by radicals originating from hydrogen peroxide. Our results indicate that ascorbate at the chosen concentration has an antioxidant effect on red blood cell lipid peroxidation.

Ascorbic Acid↗
PubMed1987

The relationship between lipid composition of red blood cells and their susceptibility to lipid peroxidation.

Red blood cells from 31 healthy donors were examined for the cholesterol content, the fatty acid composition, and the susceptibility to lipid peroxidation induced by either hydrogen peroxide or phenylhydrazine. Lipid peroxidation was monitored by the release of pentane and ethane. In addition, plasma fatty acids were measured in order to find out, whether plasma and red cell fatty acids were correlated. In experiments with hydrogen peroxide, a significant positive correlation was found between the proportion of arachidonic acid (C 20:4n - 6; r = 0.57, p less than 0.01) and docosahexaenoic acid (C 22:6n - 3; r = +0.71, p less than 0.01), and the release of pentane and ethane, respectively. A significant negative correlation was found between the membrane cholesterol content and the pentane release (r -0.44, p less than 0.05). In experiments performed with phenylhydrazine, red cell membrane lipid composition did not influence the susceptibility of red cells to lipid peroxidation. A close correlation was found between plasma and red cell fatty acids (palmitic acid, r = +0.46, p less than 0.01; linoleic acid, r = +0.41, p less than 0.05; arachidonic acid, r = +0.59, p less than 0.01; docosahexaenoic acid, r = +0.67, p less than 0.01). The results demonstrated that the degree of peroxide-induced oxidation of erythrocyte lipids depends on the content of polyunsaturated fatty acids in the membrane, which on the other hand, is determined by plasma fatty acids. It is suggested that dietary variations may influence the susceptibility of red cells to lipid peroxidation.

Adult↗
PubMed1995

Effect of alpha-tocopherol on antioxidants, lipid peroxidation, and the incidence of pulmonary hypertension syndrome (ascites) in broilers.

Research has demonstrated a compromised antioxidant capacity in broilers with pulmonary hypertension syndrome (PHS). Thus, the objective of the present study was to assess the effects of vitamin E on PHS-induced mortality, tissue antioxidants, and plasma lipid peroxides in male broilers. Control broilers were provided normal ventilation but others, maintained under low ventilation conditions to induce PHS, were randomly assigned to nonimplanted (NI), placebo (PL), or vitamin E (VE) implanted groups. The VE implant released a total of 15 mg of alpha-tocopherol from 0 to 3 wk of age. Tissues and blood samples were obtained at 3 and 5 wk of age from birds with (PHS+) and without (PHS-) PHS. Five-week PHS cumulative mortality was lowered by alpha-tocopherol with mortality rates of 3.6, 4.2, 11.9, and 11.8%, for Controls, VE, NI, and PL groups, respectively. The PHS+ birds exhibited lower body weights, higher hematocrit, right ventricular hypertrophy, lower alpha-tocopherol and glutathione (GSH) concentrations in liver and lung, as well as indicators of oxidative stress, including elevated plasma lipid peroxides and lower oxidized GSH in liver and erythrocytes, at 5 wk of age. All birds exhibited lower erythrocyte catalase activity at 5 than at 3 wk of age. An improved antioxidant capacity was observed in VE birds, including higher liver and lung alpha-tocopherol at 3 and 5 wk, higher liver GSH at 3 wk, and lower plasma lipid peroxide values at 5 wk of age. Direct correlations observed between body weight and plasma lipid peroxides at 3 wk (r = .45) and between right ventricular hypertrophy and plasma lipid peroxides at 5 wk (r = .48), suggests that lipid peroxidation plays a role in the etiology of PHS. The results indicate that the VE implant was effective in lowering PHS-induced mortality in broilers apparently by attenuating processes leading to lipid peroxidation.

Analysis of Variance↗
PubMed1992

Lipid peroxidation in rod outer segments. Role of hydroxyl radical and lipid hydroperoxides.

Lipid peroxidation of rod outer segment (ROS) membranes has been implicated in the pathogenesis of numerous ocular disease processes. The hydroxyl radical might be involved in initiating the reaction. An in vitro system was developed to study lipid peroxidation of the ROS and the role of the hydroxyl radical. Bovine ROS were suspended in various concentrations of ferrous sulfate, incubated for 10 min at 37 degrees C, treated with diethylenetriamine pentaacetic acid to chelate the iron, and subjected to a thiobarbituric acid assay for malondialdehyde. A predictable increase in lipid peroxidation occurred in the presence of Fe+2. No effect was seen in the presence of Fe+3. Adding hydrogen peroxide, which would form the hydroxyl radical by reacting with Fe+2, had no effect at low concentrations. At higher concentrations, lipid peroxidation was inhibited, presumably from the oxidation of Fe+2 to Fe+3. Ethanol, a known hydroxyl radical scavenger, had no inhibitory effect in concentrations up to 0.50 mol/l. Conversely, cumene hydroperoxide and linoleic acid hydroperoxide, which form hydrophobic radicals, stimulated lipid peroxidation in the presence of Fe+2. These findings suggest that, under these experimental conditions, the hydroxyl radical is not an initiator of lipid peroxidation in ROS. They provide evidence that endogenous lipid radicals may initiate the reaction.

Animals↗
PubMedDate not supplied

The effect of 10% carbamide peroxide, carbopol and/or glycerin on enamel and dentin microhardness.

This study evaluated the effects of 10% carbamide peroxide, carbopol and glycerin and their associations on microhardness over time on enamel and dentin. Eight treatment agents were evaluated: a commercial bleaching agent containing 10% carbamide peroxide (Opalescence 10% Ultradent), 10% carbamide peroxide, carbopol, glycerin, 10% carbamide peroxide + carbopol, 10% carbamide peroxide + glycerin, carbopol + glycerin and 10% carbamide peroxide + carbopol + glycerin. Three hundred and twenty human dental fragments, 80 sound enamel fragments (SE), 80 demineralized enamel fragments (DE), 80 sound dentin fragments (SD) and 80 demineralized dentin (DD) fragments, were exposed to the treatment agents (n=10). These agents were applied onto the surface of the fragments eight hours a day for 42 days. After eight hours, they were washed from the dental fragment surfaces after five back-and-forth movements with a soft bristle toothbrush under distilled and deionized running water. During the remaining time (16 hours per day), the fragments were kept in individual vials in artificial saliva. After the 42-day treatment period, the specimens were kept individually in artificial saliva for 14 days. Knoop microhardness measurements were performed at baseline, after eight hours, and 7, 14, 21, 28, 35 and 42 days, and 7 and 14 days post-treatment (corresponding to 49 and 56 days after the initial treatment agent applications). The non-parametric Kruskal-Wallis analysis showed significant differences among the agents at each time interval, except at baseline for sound and demineralized enamel and dentin. For SE, SD and DD, there was a decrease in microhardness values during treatment with all agents. There was a tendency towards lower microhardness values after treatment with carbopol and its associations for sound tissues. DD showed low microhardness values during and after treatment with CP and its associations. For DE, there was an increase in microhardness values during treatment with all agents and in the post-treatment phase. The baseline microhardness values were not recovered during the 14-day post-treatment phase. Opalescence 10%, carbamide peroxide, carbopol, glycerin and their associations may change the microhardness of sound and demineralized dental tissues, even in the presence of artificial saliva.

Acrylic Resins↗
PubMed2005

Soy intake plus moderate weight resistance exercise: effects on serum concentrations of lipid peroxides in young adult women.

AIM: Exercise can conceivably increase concentrations of lipid peroxides (by producing oxidant stress) or decrease their concentrations (by accelerating peroxide breakdown). The net effect could depend on exercise intensity and nutritional antioxidant intake. METHODS: Recreationally trained, young adult women (n=18) consumed antioxidant-rich soy protein or antioxidant-poor whey protein for 4 weeks (40 g protein/day). A moderate intensity, weight resistance exercise session was done before and after the 4 week period. Blood was drawn before each exercise session and postexercise at 0, 3 and 24 h. Serum from the pre-exercise draw was analyzed for antioxidant status (based on radical scavenging capacities); serum from pre- and postexercise draws were analyzed for concentrations of lipid peroxides as well as creatine kinase activities (which are affected by oxidant damage to muscles). RESULTS: Soy, but not whey intake, increased pre-exercise serum antioxidant status values and inhibited exercise-induced increases in creatine kinase activities. Before soy or whey intake, serum values for lipid peroxides rose at two of the three postexercise times. After whey intake, values for lipid peroxides showed no increase at the three postexercise times. After soy treatment, values for lipid peroxides actually showed a decrease at the three postexercise times. CONCLUSIONS: Moderate intensity exercise exerted variable effects on serum lipid peroxides with decreases occurring with 4 weeks of soy intake, which also produced other antioxidant effects.

Adolescent↗
PubMed1983

Topical treatment of acne rosacea with benzoyl peroxide acetone gel.

A group of patients with acne rosacea was treated with 5 percent benzoyl peroxide acetone gel for four weeks and then with 10 percent benzoyl peroxide acetone gel for an additional four weeks. A parallel group of patients was treated with a matching placebo (acetone gel vehicle). At the end of the first four weeks of treatment the dropout rate due to lack of improvement was 23 and 63 percent for benzoyl peroxide acetone gel and placebo, respectively. Benzoyl peroxide acetone gel was superior to placebo with respect to improvement in the overall severity of the lesions when judged by photographs, and by reduction of erythema, papules, and pustules. Results after treatment with benzoyl peroxide acetone gel were better during weeks five to eight than during weeks one to four for all lesions except telangiectasia. Benzoyl peroxide acetone gel was superior to placebo when the overall responses were compared. In addition, the benzoyl peroxide acetone gel-treated group, but not the placebo-treated group, showed a significantly better response during weeks five to eight compared to weeks one to four.

Administration, Topical↗
PubMedDate not supplied

[Participation of lipid radicals and active oxygen forms in the peroxidation of microsomal membrane lipids induced by organic hydroperoxides].

The peroxidative radicals arizing after destruction of exogenous hydroperoxides catalyzed by cytochrome P-450, carried out important functions in induction of lipid peroxidation, dependent on organic hydroperoxides. Only a slight inhibitory effect of singlet oxygen and anion radicals of superoxide on organic hydroperoxide dependent process of lipid peroxidation suggested that these active forms of oxygen participated apparently in lipid peroxidation. The traps of hydroxyl radicals (.OH) did not affect the lipid peroxidation induced by organic hydroperoxides. A mechanism is discussed for generation and function of peroxidative radicals as well as of active oxygen forms in lipid peroxidation, induced by organic hydroperoxides in liver microsomal membranes.

Animals↗
PubMed1993

Role of lipid peroxidation in tert-butylhydroperoxide-induced inhibition of endothelial cell calcium signaling.

The potential of lipid peroxidation in inhibition of Ca++ signaling by the membrane-permeant oxidant, tertiary butylhydroperoxide (tert-buOOH), was investigated in calf pulmonary vascular endothelial cells. The oxidant dose-dependently increased lipid peroxidation between concentrations of 10(-5) and 10(-3) M, with an ED50 of approximately 0.05 mM. In addition, the effect of tert-buOOH was time-dependent through the experimental period (3 h). Preincubation of cells with the 21-amino-steroid compound, 21-[4-(5,6-bis(diethylamino)-2-pyridinyl)-1-piperazinyl]-16 alpha-methyl-pregna-1,4,9(11)-triene-3,20-dione hydrochloride (U74500A), reduced tert-buOOH-induced lipid peroxidation to undetectable levels. The effect of U74500A was dose dependent with an IC50 of approximately 10(-6) M. Brief incubation of cells with the aminosteroid resulted in greater than 90% inhibition of lipid peroxidation during subsequent 2-h incubations with tert-buOOH and addition of U74500A during treatment of cells with tert-buOOH halted further lipid peroxidation. In contrast, the iron-containing moiety, hemin, potentiated the effect of tert-buOOH on lipid peroxidation. The ED50 of hemin was approximately 10(-6) M when cells were preincubated with this agent before treatment with tert-buOOH. The potentiating effect of hemin was time-dependent and reached a near maximum upon incubation of cells for 1 h before tert-buOOH. Preincubation of cells with U74500A before treatment with hemin and tert-buOOH decreased lipid peroxidation by 75%. Ca++ signaling was monitored in-cells loaded with the Ca(++)-sensitive fluorescent indicator, fura-2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Separation of pigmented and albino melanocytes and the concomitant evaluation of endogenous peroxide content using flow cytometry.

Flow cytometry (FCM) has been used extensively to analyze various biological properties of the cell. In this report, we describe a method by which FCM was used to determine the light scattering profile of a mixed population of pigmented and non-pigmented melanocytes, plus its subsequent use for the sorting and separation of the two cell types. In addition, the relative peroxide content in pigmented and non-pigmented melanocytes was compared by flow cytometry. Cultured avian melanocytes from a pigmented control and from three genetically distinct albino sources were studied. FCM analysis of forward versus side light scatter within a mixed suspension of pigmented and amelanotic melanocytes distinguished two overlapping populations of cells. Sorting of these two populations demonstrated that the population exhibiting much side and minimal forward light scatter was primarily pigmented melanocytes, while conversely the population exhibiting less side and more forward scatter was principally non-pigmented cells. These two melanocyte types also demonstrated differences in levels of endogenous peroxides. The intracellular content of peroxide in the two subpopulations of cells was measured utilizing the nonfluorescent compound, 2',7'-dichlorofluorescein diacetate (DCFH-DA), which within the cell is oxidized by intracellular peroxides to a fluorescent dichlorofluorescein (DCF). Non-pigmented albino melanocytes had the highest quantity of endogenous peroxides, while heavily pigmented cells had considerably less peroxide-related fluorescence. The amount of this DCF fluorescence could be enhanced by increasing concentrations of DCF used in the assay. These flow cytometric methods are useful for isolating and culturing subpopulations of melanocytes expressing various pigment levels and to investigate the relationship between melanin and its precursors with hydrogen and lipid peroxides in melanocytes.

Animals↗
PubMed1993

Characterization of hypoxia-dependent peroxide production in cultures of Saccharomyces cerevisiae using flow cytometry: a model for ischemic tissue destruction.

Peroxide production in cultures of Saccharomyces cerevisiae was measured using the H2O2-sensitive fluorescent probe 2',7'-dichlorofluorescein diacetate (DCFH-DA) and flow cytometry. Aeration of cultures of S. cerevisiae exposed to a period of hypoxia was found to induce elevated levels of peroxide that were 100-fold higher than the levels observed in cultures maintained under exclusively aerated or hypoxic conditions. Simultaneous viability analysis, using the fluorescent DNA-intercalating dye propidium iodide, indicated that the increase in peroxide generation preceded cell damage and death. Various agents were found to influence the effect of peroxides on cell viability. The addition of ethanol to hypoxic stationary cultures dramatically increased the rate of cell death without further increasing the amount of peroxide produced, while glucose inhibited peroxide production and decreased the rate of cell death. Surprisingly, elevated peroxide levels of hypoxic/reaerated cultures were maintained upon addition of KH2PO4, although the cells remained viable for extended periods of time when compared to control and other test cultures. Similarities between our observations and those of other investigators using anoxic/reperfused organs suggest that hypoxic/reaerated yeast cultures may be a useful model system to study ischemia-dependent tissue destruction of mammals.

Cell Death↗
PubMedDate not supplied

In vitro exposure to quercetin and genistein alters lipid peroxides and prevents the loss of glutathione in human progenitor mononuclear (U937) cells.

The effects of flavonoids quercetin and genistein were investigated according to their potency to inhibit the oxidation of U937 cells via Fenton's pathway through the analysis of lipid peroxides and glutathione (GSH) levels. Human leukemia (U937) cells from the American Type Culture Collection were maintained at 37 degrees C for 24 h under 5% CO2 tension in RPMI-1640 medium containing 10% fetal bovine serum and 50 units ml(-1) each of penicillin and streptomycin. Cells were oxidized with iron 50 microM) or copper (50 microM) in H2O2 (0.01 mM) without or with a flavonoid sample (10 or 20 microM) for the lipid peroxidation studies. The GSH levels were measured (GSH Kit) before and after oxidation as above with different concentrations of flavonoids (0-40 microM). Lipid peroxide was measured by the thiobarbituric acid assay. Both quercetin and genistein at either the 10 or 20 microM level decreased lipid peroxidation significantly compared with their respective controls (P < 0.01). Lipid peroxides by Fe compared to the Cu-treated samples did not differ significantly from each other. However, the combination of flavonoids at the doses tested significantly (P < 0.001) decreased lipid peroxides, the effect being the same for both metal ions. The GSH levels increased significantly before exposure to the metal ions (for the different doses for the differences between the flavonoid samples and their respective untreated levels). For quercetin and genistein the increases in GSH above their untreated levels were 4.5, 8.3, 11.7 and 15 and 3.8, 7.9, 12.5 and 14.6 nmol 10(-6) cells, respectively, for the 5-40 microM levels tested for each flavonoid. Following the exposure to the metal ions, GSH levels remained almost the same for the different concentrations for each of the flavonoids tested but significantly above all of the controls and same for those of the untreated samples. The results indicate that both flavonoids inhibited lipid peroxides and the inhibition may be attributed to the prevention of loss of intracellular GSH levels in U937 cells.

Antioxidants↗
PubMed2004

Effect of alpha-tocopherol and N-acetylcysteine on benzoyl peroxide toxicity in human keratinocytes.

Benzoyl peroxide is a free-radical generating compound widely used in the polymer industry and also in pharmaceuticals as antimicrobial agent to treat acne. However, benzoyl peroxide causes irritation and contact dermatitis in about 1% of patients. Concern over the use of this compound is motivated by the demonstration that it can also act as skin tumor promoter in mice. In addition, benzoyl peroxide induces DNA strand breaks in many cells, including keratinocytes. Benzoyl peroxide toxicity is presumably mediated by the formation of reactive free radicals and by the consumption of intracellular antioxidants. In this work we investigated the effect of both the lipophilic antioxidant alpha-tocopherol and the hydrophilic thiol donor N-acetylcysteine (NAC) in human keratinocyte line HaCaT exposed to benzoyl peroxide. A protective effect against benzoyl peroxide cytotoxicity was achieved when cells were grown on a alpha-tocopherol layer. On the contrary, the addition of alpha-tocopherol dissolved in ethanol had a pro-oxidant effect, leading to an enhancement of benzoyl peroxide toxicity. Cytotoxicity was also reduced adding NAC to the culture medium; the presence of both NAC and alpha-tocopherol exerts a synergistic cytoprotection.

Acetylcysteine↗
PubMed1991

Role of cytochrome P-450 in ochratoxin A-stimulated lipid peroxidation.

The role of cytochrome P-450 in the stimulation of lipid peroxidation by the nephrotoxic mycotoxin ochratoxin A has been investigated. Ochratoxin A was previously shown to markedly stimulate lipid peroxidation in a reconstituted system consisting of phospholipid vesicles, NADPH-cytochrome P-450 reductase, Fe3+, ethylenediaminetetraacetic acid (EDTA), and reduced nicotinamide adenine dinucleotide phosphate (NADPH). We now show that purified cytochrome P-450IIB1 could effectively replace EDTA in stimulating lipid peroxidation suggesting that it could mediate the transfer of electrons from NADPH to Fe3+. Cobalt protoporphyrin is known to cause an extensive and long-lasting depletion of hepatic cytochrome P-450 in rats, and it has been used to evaluate the role of hepatic cytochrome P-450 in xenobiotic metabolism and toxicity. We have observed that microsomes isolated from livers of cobalt protoporphyrin-pretreated rats underwent ochratoxin A-dependent lipid peroxidation much more slowly than control microsomes. Also, the level of ethane exhaled (an index of in vivo lipid peroxidation) on ochratoxin A administration was much lower in cobalt protoporphyrin-pretreated rats than in control rats. Taken together, these results provide evidence for the stimulatory role of cytochrome P-450 in ochratoxin A-induced lipid peroxidation in a reconstituted system and strongly implicate its role in microsomal and in vivo ochratoxin A-induced lipid peroxidation.

Animals↗
PubMed2004

Synthetic peroxides as antimalarials.

The discovery of artemisinin in 1971 initiated a new era in antimalarial chemotherapy. Although the clinically useful semisynthetic artemisinin derivatives are rapid acting and potent antimalarial drugs, they have short half-lives and must be administered over a period of 5-7 days, leading to noncompliance and recrudescence. With this in view, many synthetic antimalarial peroxides have been prepared. Yet, identification of orally active synthetic peroxide drug development candidates that are easily synthesized, inexpensive, and with good biopharmaceutical properties has been surprisingly difficult. In this review, we document the pitfalls and progress made in this endeavor. For each of 15 synthetic peroxide structural classes, we note highlights of the synthetic routes, product stereochemistry, and origin of the peroxide O atoms. Both in vitro and in vivo antimalarial data are then discussed and any SAR noted. Available data indicates that several synthetic 1,2,4-trioxanes are only marginally less effective than the semisynthetic artemisinins. Within a given peroxide chemical family, the more lipophilic members are more potent and possess better oral antimalarial activity in animal models than their more polar counterparts. This poses a challenge to identify peroxide structures with suitable "drug-like" physicochemical properties. Nonetheless, substantial progress has been made in the identification of a new generation of synthetic antimalarial peroxides.

Antimalarials↗