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Biomedical subjects

E A Serbinova

Publications and source records attributed to E A Serbinova.

At least 19 recordsLinked to original sources
PubMed1992

Antiradical effects in L-propionyl carnitine protection of the heart against ischemia-reperfusion injury: the possible role of iron chelation.

L-Propionyl carnitine has been shown to improve the heart's mechanical recovery and other metabolic parameters after ischemia-reperfusion. However, the mechanism of protection is unknown. The two dominating hypotheses are: (i) L-propionyl carnitine can serve as an energy source for heart muscle cells by being enzymatically converted to propionyl-CoA and subsequently utilized in the Krebs cycle (a metabolic hypothesis), and (ii) it can act as an antiradical agent, protecting myocardial cells from oxidative damage (a free radical hypothesis). To test the two possible pathways, we compared the protection afforded to the ischemia-reperfused hearts by L-propionyl carnitine and its optical isomer, D-propionyl carnitine. The latter cannot be enzymatically utilized as an energy source. The Langendorff perfusion technique was used and the hearts were subjected to 40 min of ischemia and 20 min of reperfusion. In analysis of ischemia-reperfused hearts, a strong correlation was found between the recovery of mechanical function and the presence of protein oxidation products (protein carbonyls). Both propionyl carnitines efficiently prevented protein oxidation but L-propionyl carnitine-perfused hearts had two times greater left ventricular developed pressure. The results indicate that both metabolic and antiradical pathway are involved in the protective mechanism of L-propionyl carnitine. To obtain a better insight of the antiradical mechanism of L-propionyl carnitine, we compared the ability of L- and D-propionyl carnitines, L-carnitine, and deferoxamine to interact with: (i) peroxyl radicals, (ii) oxygen radicals, and (iii) iron. We found that none of the carnitine derivatives were able to scavenge peroxyl radicals or superoxide radicals. L- and D-propionyl carnitine and deferoxamine (not L-carnitine) suppressed hydroxyl radical production in the Fenton system, probably by chelating the iron required for the generation of hydroxyl radicals. We suggest that L-propionyl carnitine protects the heart by a dual mechanism: it is an efficient fuel source and an antiradical agent.

Animals↗
PubMed1992

NADPH-dependent inhibition of lipid peroxidation in rat liver microsomes.

Microsomal NADPH-driven electron transport is known to initiate lipid peroxidation by activating oxygen in the presence of iron. This pro-oxidant effect can mask an antioxidant function of NADPH-driven electron transport in microsomes via vitamin E recycling from its phenoxyl radicals formed in the course of peroxidation. To test this hypothesis we studied the effects of NADPH on the endogenous vitamin E content and lipid peroxidation induced in liver microsomes by an oxidation system independent of iron: an azo-initiator of peroxyl radicals, 2,2'-azobis (2,4-dimethylvaleronitrile), (AMVN), in the presence of an iron chelator deferoxamine. We found that under conditions NADPH: (i) inhibited lipid peroxidation; (ii) this inhibitory effect was less pronounced in microsomes from vitamin E-deficient rats than in microsomes from normal rats; (iii) protected vitamin E from oxidative destruction; (iv) reduced chromanoxyl radicals of vitamin E homologue with a 6-carbon side-chain, chromanol-alpha-C-6. Thus NADPH-driven electron transport may function both to initiate and/or inhibit lipid peroxidation in microsomes depending on the availability of transition metal catalysts.

Animals↗
PubMed1992

Recycling of vitamin E in human low density lipoproteins.

Oxidative modification of low density lipoproteins (LDL) and their unrestricted scavenger receptor-dependent uptake is believed to account for cholesterol deposition in macrophage-derived foam cells. It has been suggested that vitamin E that is transported by LDL plays a critical role in protecting against LDL oxidation. We hypothesize that the maintenance of sufficiently high vitamin E concentrations in LDL can be achieved by reducing its chromanoxyl radicals, i.e., by vitamin E recycling. In this study we demonstrate that: i) chromanoxyl radicals of endogenous vitamin E and of exogenously added alpha-tocotrienol, alpha-tocopherol or its synthetic homologue with a 6-carbon side-chain, chromanol-alpha-C6, can be directly generated in human LDL by ultraviolet (UV) light, or by interaction with peroxyl radicals produced either by an enzymic oxidation system (lipoxygenase + linolenic acid) or by an azo-initiator, 2,2'-azo-bis(2,4-dimethylvaleronitrile) (AMVN; ii) ascorbate can recycle endogenous vitamin E and exogenously added chromanols by direct reduction of chromanoxyl radicals in LDL; iii) dihydrolipoic acid is not efficient in direct reduction of chromanoxyl radicals but recycles vitamin E by synergistically interacting with ascorbate (reduces dehydroascorbate thus maintaining the steady-state concentration of ascorbate); and iv) beta-carotene is not active in vitamin E recycling but may itself be protected against oxidative destruction by the reductants of chromanoxyl radicals. We suggest that the recycling of vitamin E and other phenolic antioxidants by plasma reductants may be an important mechanism for the enhanced antioxidant protection of LDL.

Ascorbic Acid↗
PubMed1990

Mechanisms of stabilization of biomembranes by alpha-tocopherol. The role of the hydrocarbon chain in the inhibition of lipid peroxidation.

The effects of alpha-tocopherol and its homologues with different chain lengths (6-hydroxy-chromanes: C1, C6, C11) on lipid peroxidation in natural membranes (liver microsomes and mitochondria, brain synaptosomes) and liposomes were studied. It was shown that the antioxidant activity of alpha-tocopherol homologues decreased in the order: C1 greater than C6 greater than C11 greater than alpha-tocopherol (C16). Using fluorescent measurements, the possible reasons underlying these differences were investigated: (i) the distribution between the aqueous media and nonpolar phase of the membrane, which predetermines the binding of alpha-tocopherol homologues to membranes; (ii) the incorporation of alpha-tocopherol homologues into lipid bilayer; (iii) non-uniform distribution (formation of the clusters) of tocopherol homologues in the lipid bilayer; and (iv) transbilayer mobility of alpha-tocopherol homologues and accessibility of the inhibitors for radical-generating centres under enzymically and non-enzymically induced lipid peroxidation. It was demonstrated that: (i) binding of C1 with membranes was less efficient than that of longer-chain homologues (C6, C11, C16); (ii) the level of incorporation of alpha-tocopherol homologues into membranes decreased in a succession alpha-tocopherol C11 greater than C6 greater than C1; (iii) all alpha-tocopherol homologues existed in the lipid bilayer not only in a monomeric form but also associated in clusters thus decreasing the efficiency of radical scavenging; (iv) the short-chain alpha-tocopherol homologue, C1, exhibited a high transbilayer mobility whereas the long-chain one, C16, underwent no transbilayer migration within tens of minutes. The inhibiting effect of alpha-tocopherol esters and C1-acetate was predetermined by their hydrolysis in biomembranes; a strong correlation exists between the rate of the ester hydrolysis and their antioxidant activity in the membrane. In liposomes, in which the esterase activity was absent, alpha-tocopherol esters and C1-acetate exhibited very low lipid peroxidation inhibition.

Animals↗
PubMed1990

Recycling and antioxidant activity of tocopherol homologs of differing hydrocarbon chain lengths in liver microsomes.

Tocopherols (vitamin E) function as inhibitors of lipid peroxidation in biomembranes by donating a hydrogen atom to the chain propagating lipid radicals, thus giving rise to chromanoxyl radicals of the antioxidant. We have shown that alpha-tocopherol homologs differing in the lengths of their hydrocarbon side chains (alpha-Cn) manifest strikingly different antioxidant potencies in membranes. The antioxidant activity of tocopherol homologs during (Fe2+ + ascorbate)- or (Fe2+ + NADPH)-induced lipid peroxidation in rat liver microsomes increased in the order alpha-tocopherol (alpha-C16) less than alpha-C11 less than alpha-C6 less than alpha-C1. Chromanoxyl radicals generated from alpha-tocopherol and its more polar homologs by an enzymatic oxidation system (lipoxygenase + linolenic acid) can be recycled in rat liver microsomes by NAD-PH-dependent electron transport or by ascorbate. The efficiency of recycling increased in the same order: alpha-tocopherol (alpha-C16) less than alpha-C11 less than alpha-C6 less than alpha-C1. Thus the high efficiency of regeneration of short-chain homologs of vitamin E may account for their high antioxidant potency.

Animals↗
PubMed1990

Generation and recycling of radicals from phenolic antioxidants.

Hindered phenols are widely used food preservatives. Their pharmacological properties are usually attributed to high antioxidant activity due to efficient scavenging of free radicals. Butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA) also cause tissue damage. Their toxic effects could be due to the production of phenoxyl radicals. If phenoxyl radicals can be recycled by reductants or electron transport, their potentially harmful side reactions would be minimized. A simple and convenient method to follow phenoxyl radical reactions in liposomes and rat liver microsomes based on an enzymatic (lipoxygenase + linolenic acid) oxidation system was used to generate phenoxyl radicals from BHT and its homologues with substitutents in m- and p-positions. Different BHT-homologues display characteristic ESR signals of their radical species. In a few instances the absence of phenoxyl radical ESR signals was found to be due to inhibition of lipoxygenase by BHT-homologues. In liposome or microsome suspensions addition of ascorbyl palmitate resulted in disappearance of the ESR signal of phenoxyl radicals with concomittant appearance of the ascorbyl radical signal. After exhaustion of ascorbate, the phenoxyl radical signal reappears. Comparison of the rates of ascorbyl radical decay in the presence or absence of BHT-homologues showed that temporary elimination of the phenoxyl radical ESR signal was due to their reduction by ascorbate. Similarly, NADPH or NADH caused temporary elimination of ESR signals as a result of reduction of phenoxyl radicals in microsomes. Since ascorbate and NADPH might generate superoxide in the incubation system used, SOD was tested. SOD shortened the period, during which the phenoxyl radicals ESR signal could not be observed. Both ascorbyl palmitate and NADPH exerted sparing effects on the loss of BHT-homologues during oxidation. These effects were partly diminished by SOD. These data indicate that reduction of phenoxyl radicals was partly superoxide-dependent. It is concluded that redox recycling of phenoxyl radicals can occur by intracellular reductants like ascorbate and microsomal electron transport.

Animals↗
PubMed1990

Intermembrane transfer and antioxidant action of alpha-tocopherol in liposomes.

Intermembrane transfer and exchange of tocopherol are not well understood. To study this we tested the ability of alpha-tocopherol containing unilamellar donor liposomes to inhibit the accumulation of lipid peroxidation products in acceptor liposomes. With molar ratios of alpha-tocopherol:phospholipids from 1:100 to 1:1000 in donor liposomes prepared by sonication of lipid dispersions, alpha-tocopherol was incorporated into both monolayers and was homogenously distributed in monomeric form without forming clusters in the liposomes. Concentrations of alpha-tocopherol which completely prevented the peroxidation of lipids were chosen for donor liposomes. Hence inhibition of lipid peroxidation in mixtures of donor and acceptor liposomes was determined by the antioxidant effect of alpha-tocopherol in acceptor liposomes which resulted from intermembrane transfer and exchange of alpha-tocopherol. Evidence was obtained that this was not due to fusion of donor with acceptor liposomes. The efficiency of the "intermembrane" antioxidant action of tocopherol was more pronounced when donor liposomes contained unsaturated phospholipids, indicating that the presence of unsaturated fatty acids in the outer monolayer phospholipids facilitates intermembrane tocopherol exchange.

Animals↗
PubMed1990

Antioxidant action of ubiquinol homologues with different isoprenoid chain length in biomembranes.

Ubiquinones (CoQn) are intrinsic lipid components of many membranes. Besides their role in electron-transfer reactions they may act as free radical scavengers, yet their antioxidant function has received relatively little study. The efficiency of ubiquinols of varying isoprenoid chain length (from Q0 to Q10) in preventing (Fe2+ + ascorbate)-dependent or (Fe2+ + NADPH)-dependent lipid peroxidation was investigated in rat liver microsomes and brain synaptosomes and mitochondria. Ubiquinols, the reduced forms of CoQn, possess much greater antioxidant activity than the oxidized ubiquinone forms. In homogenous solution the radical scavenging activity of ubiquinol homologues does not depend on the length of their isoprenoid chain. However in membranes ubiquinols with short isoprenoid chains (Q1-Q4) are much more potent inhibitors of lipid peroxidation than the longer chain homologues (Q5-Q10). It is found that: i) the inhibitory action, that is, antioxidant efficiency of short-chain ubiquinols decreases in order Q1 greater than Q2 greater than Q3 greater than Q4; ii) the antioxidant efficiency of long-chain ubiquinols is only slightly dependent on their concentrations in the order Q5 greater than Q6 greater than Q7 greater than Q8 greater than Q9 greater than Q10 and iii) the antioxidant efficiency of Q0 is markedly less than that of other homologues. Interaction of ubiquinols with oxygen radicals was followed by their effects on luminol-activated chemiluminescence. Ubiquinols Q1-Q4 at 0.1 mM completely inhibit the luminol-activated NADPH-dependent chemiluminescent response of microsomes, while homologues Q6-Q10 exert no effect. In contrast to ubiquinol Q10 (ubiquinone Q10) ubiquinone Q1 synergistically enhances NADPH-dependent regeneration of endogenous vitamin E in microsomes thus providing for higher antioxidant protection against lipid peroxidation. The differences in the antioxidant potency of ubiquinols in membranes are suggested to result from differences in partitioning into membranes, intramembrane mobility and non-uniform distribution of ubiquinols resulting in differing efficiency of interaction with oxygen and lipid radicals as well as different efficiency of ubiquinols in regeneration of endogenous vitamin E.

Animals↗
PubMed1990

[Intermembrane transport and antioxidant action of alpha-tocopherol in liposomes].

Studies were made of the ability of alpha-tocopherol, incorporated into unilamellar liposomes from saturated or unsaturated phospholipids (donor liposomes) to inhibit the accumulation of lipid peroxidation (LPO) products in unilamellar liposomes from rat cerebral cortex lipids (acceptor liposomes) in the presence of LPO inducer (Fe + ascorbate). With the molar alpha-tocopherol: phospholipids rations from 1:1000 to 1:100 in donor liposomes, obtained through sonication of lipid dispersions, alpha-tocopherol was incorporated into both monolayers of liposomes and was distributed in monomeric form without forming clusters. Based on the dependencies of LPO inhibition on the alpha-tocopherol concentrations, we chose the ones that completely prevented the accumulation of LPO products in donor liposomes. Under these conditions LPO inhibition in mixtures of donor and acceptors liposomes was fully determined by the antioxidant effect of alpha-tocopherol in acceptor liposomes due to its intermembrane transfer. The efficiency of the "intermembrane" antioxidant action of alpha-tocopherol increased in the course of preincubation of donor and acceptor liposomes (up to 60 min) and this increase was more pronounced when the donor liposomes contained unsaturated phospholipids. Evidence was obtained that the intermembrane transfer of alpha-tocopherol did not result from the fusion of donor and acceptor liposomes during preincubation.

Animals↗
PubMed1989

Lipid peroxidation activation and cytochrome P-450 decrease in rat liver endoplasmic reticulum under oxidative stress.

Iron loading was associated with development of oxidative stress, viz, decrease in tocopherol content and an increase in amount of lipid peroxidation products but only slight, if any, decrease in cytochrome P-450 content. Combinations of iron loading with other stress-inducing treatments (exhaustive physical exercise and hyperoxia) caused marked decreases in cytochrome P-450 content. Thus, a combination of factors favoring development of oxidative stress, but insufficient to exert a damaging effect on the cytochrome P-450-dependent detoxification system when acting alone, may become quite potent when acting in concert.

Animals↗
PubMed1989

[The action of a homologous series of ubiquinols on lipid peroxidation in brain mitochondrial and synaptosomal membranes].

The effects of inhibition of ubiquinols and ubiquinones with various length of isoprenoid chain on the lipid peroxidation in membranes of brain mitochondria and synaptosomes were studied. The efficiency of inhibition effects of ubiquinols depends on the length of isoprenoid chain. Ubiquinols with shorter isoprenoid chains demonstrated more effective inhibition.

Animals↗
PubMed1988

The role of secondary messengers in the regulation of lipid peroxidation in rat liver microsomes.

The effect of phorbol-12-myristate-13-acetate (PMA), an activator of protein kinase C (PK-C) on lipid peroxidation (LPO) in rat liver homogenates and microsomes was studied. PMA (10(-10) to 10(-6) M) produced a concentration-dependent inhibition of LPO, which was greatly decreased by polymyxin B (PxB) (an inhibitor of PK-C). The non-active analogue of PMA, 4 alpha-phorbol-12,13-didecanoate (4 alpha-PDD) exerted no inhibitory effect. The adenylate cyclase activator, forskolin (FK) (10(-6) M) abolished the inhibitory effect of PMA on LPO. PMA and FK did not inhibit LPO in liposomes. It is suggested that LPO in biomembranes could be regulated by PK-C, whose inhibitory effect might be prevented by cAMP-dependent protein kinases.

Animals↗
PubMed1986

[Effectiveness of lipid peroxidation inhibition in biomembranes by antioxidants with and without hydrocarbon chains].

The efficacy of lipid peroxidation inhibition by the natural antioxidant alpha-tocopherol and 2,2,5,7,8-pentamethyl-6-hydroxy-chromane (PMC), a derivative without hydrocarbon tail, as well as by the synthetic antioxidant 4-methyl-2,6-diterbutyl phenol (BHT) and its phospholipid derivative was studied in the membranes of rat liver microsomes and mitochondria. The presence of hydrocarbon tail in the antioxidant molecule determines the decrease of antioxidant efficiency in biomembranes. PMC and BHT exert a destructive effect on biomembranes, leading to an increase in their permeability to ions. This evidence suggests that the presence of hydrocarbon tail in the molecules of natural antioxidants provides not only for a relatively high antioxidant efficiency but also for a structural stability of biomembranes.

Animals↗
PubMed1986

[The interaction of alpha-tocopherol with phospholipid liposomes: the absence of transbilayer mobility].

The interaction of alpha-tocopherol with liposomes obtained from saturated and unsaturated phospholipids and the rate of its flip-flop were studied using fluorescent technique. It was found that the amount of alpha-tocopherol introduced into outer and inner monolayers remained unchanged for many hours. No migration from the outer to the inner monolayers and vice versa was observed. The effect did not depend on the fatty acid phospholipid composition. The results obtained are considered in view of the optimal conditions of membrane tissue saturation with liposome-incorporated tocopherol.

Drug Interactions↗