脂质过氧化引起的DNA损伤研究进展

脂质过氧化可以引起各种碱基损伤、DNA链断裂和各种荧光产物生成,并对DNA分子鸟嘌呤碱基具有选择性损伤.过渡金属离子可以明显加深脂质过氧化对DNA的损伤程度.多种抗氧化剂、活性氧自由基清除剂对脂质过氧化引起的DNA损伤有一定程度的保护作用.具有致突、致癌作用的8－羟基鸟嘌呤已经观察到．脂质过氧化的致突变、致癌变作用机制引起了人们的极大兴趣．     

Inhibition of protein synthesis by products of lipid peroxidation

Effects of lipid peroxidation products on in vivo and in vitro protein synthesis have been studied. Malondialdehyde (MDA), a product, and a routinely used index of lipid peroxidation, inhibits in vivo protein synthesis in the two mosses, Tortula ruralis and Cratoneuron filicinum, and in pea (Pisum sativum) leaf discs. When wheat germ supernatant or poly(A)-rich mRNA of T. ruralis was incubated with MDA its subsequent activity in a cell-free protein-synthesizing system was reduced. When MDA was added directly to the in vitro protein-synthesizing mixture containing moss polyribosomes, the inhibition of amino acid incorporation was small. However, when simultaneous lipid peroxidation was allowed to occur along with in vitro protein synthesis there was a strong inhibition of amino acid incorporation and MDA accumulated in the reaction mixture indicating that products of lipid peroxidation other than, and apparently more toxic than, MDA were involved. It was concluded that lipid peroxidation inhibits protein synthesis probably by releasing toxic products which may react with and inactivate some components of the protein-synthesizing complex.     

Aldehyde adducts generated during lipid peroxidation modification of proteins

Abstract

Various lines of evidence indicate that an important part in the pathogenesis of atherosclerosis is the modification of the plasma low-density lipoproteins (LDLs). A large number of pro-inflammatory and pro-atherogenic properties have been ascribed to the oxidatively modified LDLs and their components. There is considerable evidence to support the role of lipid peroxidation products, reactive aldehydes in particular, originating from the oxidized LDL as important signaling molecules in the context of the atherosclerotic lesion. These aldehydes generated during the peroxidation of LDL exhibit a facile reactivity with proteins, generating a variety of intra- and intermolecular covalent adducts on the apolipoprotein B-100 particle in LDL. Characterization of the aldehyde adducts generated in the protein is therefore critical in understanding the nature of the oxidized LDL. However, the majority of adducts generated during the oxidative modification of LDL have not yet been chemically characterized. In this review, the current status of aldehyde adducts quantitatively analyzed in the Cu²⁺-oxidized LDL is reviewed.     

Aldehyde reductase gene expression by lipid peroxidation end products,MDA and HNE

Membrane lipid peroxidation results in the production of a variety of aldehydic compounds that play a significant role in aging, drug toxicity and the pathogenesis of a number of human diseases, such as atherosclerosis and cancer. Increased lipid peroxidation and reduced antioxidant status may also contribute to the development of diabetic complications. This study reports that lipid peroxidation end products such as malondialdehyde (MDA) and 4-hydroxynonenal (HNE) induce aldehyde reductase (ALR) gene expression. MDA and HNE induce an increase in intracellular peroxide levels; N-Acetyl-L-cysteine (NAC) suppressed MDA- and HNE-induced ALR gene expression. These results indicate that increased levels of intracellular peroxides by MDA and HNE might be involved in the upregulation of ALR.     

Retardation of cell aging by lipid peroxidation

Different concentrations of Fe e+/vitamin C mixtures were used as initiators of lipid peroxidation in diploid fibroblasts from cultured human embryonic lung. Malondialdehyde (MDA) formation in the cell cultures was correlated directly with the concentrations of Fe²⁺ and vitamine C. Lipid peroxidation was associated with an increase in life-span, decrease in the population doubling time and increase in cellular DNA synthesis. The effects of lipid peroxidation varied inversely with the MDA level. These data showed that low levels of lipid peroxidation retarded several biological properties of cultured cells that are associated with cell aging.     

Aluminium-induced production of oxygen radicals, lipid peroxidation and DNA damage in seedlings of rice (Oryza sativa)

The effect of aluminium (Al) on seedlings of two rice cultivars, Pusa Basmati and Vikas was investigated after different hours of exposure to 80 mol/L of external Al supply. With increasing time of exposure, the growing seedlings readily absorbed Al and its localization was greater in roots than shoots. Prolonged exposure to Al intensified lipid peroxidation, changed the activities of SOD and peroxidase and caused DNA damage. However, differential responses were observed between the seedlings of two rice cultivars under Al stress. A close inverse relationship existed between decreased root growth and increased Al accumulation, lipid peroxidation, SOD, peroxidase activities and DNA damage. The results demonstrate that roots are the major sites of Al localization and accumulation of Al promoted oxygen free radicals mediated peroxidation of membranes as evidenced by increased MDA levels and the activities of SOD and peroxidase. Our results for the first time showed that Al can cause DNA damage in rice.     

Cadmium induced lipid peroxidation in rat testes and protection by selenium

The main goal of this study was to investigate the role of cadmium in the promotion of lipid peroxidation in the homogenates of rat testes and the effect of selenium on lipid peroxidation in testes of rats after cadmium injection. Treatment of rats with cadmium resulted in a time- and dose-related accumulation of the metal ions in testes. The concentrations of cadmium, copper, zinc, selenium and iron in the tissues were determined by an atomic absorption spectrophotometer and lipid peroxidation in testes was measured by a spectrophotometer. Cadmium produced enhanced lipid peroxidation in testes. These cadmium-induced changes were accompanied by a significant increase of iron and copper, and a decrease of zinc in testes. Concurrent treatment with selenium and cadmium reduced the cadmium-induced alterations in lipid peroxidation and essential metal levels. Data suggest that lipid peroxidation was associated with cadmium toxicity in testes and that the addition of selenium was found to be effective in attenuation of this effect.     

Influence of N-phthaloyl gamma-aminobutyric acid on circadian rhythms of lipid peroxidation products and antioxidants

N-Phthaloyl GABA was administrated daily (50 mg/kg body weight-i.p) to Wistar rats for 21 days and circadian rhythms of thiobarbituric acid reactive substances (TBARS) and antioxidants such as reduced glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD) were studied. N-Phthaloyl GABA was found to delay TBARS and to advance GSH, CAT and SOD acrophases. Amplitude and mesor values of these rhythms were found to be altered during N-Phthaloyl GABA treatment. Since GABA is hypothesized to be involved in conveying dark information to clock, exogenous administration of P-GABA might alter the photic information received by the clock. Our study shows that P-GABA administration alters the temporal patterns of lipid peroxidation and antioxidants in Wistar rats. But the exact mechanism remains to be explored and further research is needed.     

Assessment of growth inhibition by aldehydic lipid peroxidation products and related aldehydes by Saccharomyces cerevisiae

The effect of pretreatment with aldehydes on the subsequent colony forming efficiency (CFE) of Saccharomyces cerevisiae was investigated. All 21 aldehydes tested inhibited CFE in a dose-dependent manner. The effective doses, however, differed markedly from 300 mM to 0·07 mM depending on the functional groups and chain length of the aldehydes. Amongst the nine representatives of n-alkanals, formaldehyde was the most potent inhibitor, reducing CFE to 50 per cent at a dose of 0·3 mM (IC₅₀). In the series of 2-trans-alkenals, acrolein was most effective with an IC₅₀ of 0·08 mM and amongst the 4-hydroxy 2-trans-alkenals, 4-hydroxynonenal was most effective with IC₅₀ of 0·07 mM . In general, effectiveness decreased in the order: 4-hydroxyalkenals > 2-alkenals ? n-alkenals. It is proposed that S. cerevisiae is a promising target cell to elucidate further the molecular mechanisms by which aldehydes, particularly the lipid peroxidation product 4-hydroxynonenal, inhibits cell proliferation.     

Nonesterified fatty acids and lipid peroxidation

Oxygen free radicals damage cells through peroxidation of membrane lipids. Gastrointestinal mucosal membranes were found to be resistant to in vitro lipid peroxidation as judged by malonaldehyde and conjugated diene production and arachidonic acid depletion. The factor responsible for this in this membrane was isolated and chemically characterised as the nonesterified fatty acids (NEFA), specifically monounsaturated fatty acid, oleic acid. Authentic fatty acids when tested in vitro using liver microsomes showed similar inhibition. The possible mechanism by which NEFA inhibit peroxidation is through iron chelation and iron-fatty acid complex is incapable of inducing peroxidation. Free radicals generated independent of iron was found to induce peroxidaton of mucosal membranes. Gastrointestinal mucosal membranes were found to contain unusually large amount of NEFA. Circulating albumin is known to contain NEFA which was found to inhibit iron induced peroxidation whereas fatty acid free albumin did not have any effect. Addition of individual fatty acids to this albumin restored its inhibitory capacity among which monounsaturated fatty acids were more effective. These studies have shown that iron induced lipid peroxidation damage is prevented by the presence of nonesterified fatty acids.     

End products of lipid peroxidation in erythrocyte membranes in Alzheimer's disease

Alzheimer's disease (AD) is accompanied by oxidative stress in the brain. Because the brain tissue is rich in polyunsaturated fatty acids, it is prone to the free radical attack resulting in lipid peroxidation. Intermediates of lipid peroxidation may diffuse from the primary site, cross the blood-brain barrier and modify erythrocyte membranes in the bloodstream. We exposed isolated erythrocyte membranes from patients with AD and the control group to in vitro free radical damage and monitored the accumulation of the end products of lipid peroxidation, lipofuscin-like pigments (LFPs), by fluorescence spectroscopy. LFPs were analyzed by means of tridimensional and synchronous fluorescence spectroscopy. The levels of LFP formed during in vitro peroxidation were significantly higher in erythrocyte membranes from patients with AD compared with the control group. Furthermore, the chemical composition of LFP in AD was different from the control group. The analysis of the specific modifications of erythrocyte membranes in AD is of great medical importance regarding the need of a diagnostic blood biomarker.     

Membrane lipid peroxidation by ultrasound: Mechanism and implications

Ultrasonic radiation produced a dose-dependent linear increase in lipid peroxidation in the liposomes membrane as reflected in the measurement of conjugated dienes, lipid hydroperoxides and malondialdehydes. Ultrasound induced malondialdehyde production could not be inhibited by any significant degree by superoxide dismutase or histidine or dimethyl furan but was very significantly inhibited by butylated hydroxytoluene, cholesterol, sodium benzoate, dimethyl sulphoxide, sodium formate and EDTA. The scavenger studies indicated the functional role of hydroxyl radicals in the initiation of ultrasound induced lipid peroxidation.     

Cadmium-induced excretion of urinary lipid metabolites,DNA damage,glutathione depletion,and hepatic lipid peroxidation in sprague-dawley rats

Recent studies have described lipid peroxidation to be an early and sensitive consequence of cadmium exposure, and free radical scavengers and antioxidants have been reported to attenuate cadmium-induced toxicity. These observations suggest that cadmium produces reactive oxygen species that may mediate many of the untoward effects of cadmium. Therefore, the effects of cadmium (II) chloride on reactive oxygen species production were examined following a single oral exposure (0.50 LD₅₀) by assessing hepatic mitochondrial and microsomal lipid peroxidation, glutathione content in the liver, excretion of urinary lipid metabolites, and the incidence of hepatic nuclear DNA damage. Increases in lipid peroxidation of 4.0- and 4.2-fold occurred in hepatic mitochondria and microsomes, respectively, 48 h after the oral administration of 44 mg cadmium (II) chloride/kg, while a 65% decrease in glutathione content was observed in the liver. The urinary excretion of malondialdehyde (MDA), formaldehyde (FA), acetaldehyde (ACT), and acetone (ACON) were determined at 0–96 h after Cd administration. Between 48 and 72 h posttreatment maximal excretion of the four urinary lipid metabolites was observed with increases of 2.2- to 3.6-fold in cadmium (II) chloride-treated rats. Increases in DNA single-strand breaks of 1.7-fold were observed 48 h after administration of cadmium. These results support the hypothesis that cadmium induces production of reactive oxygen species, which may contribute to the tissue-damaging effects of this metal ion.     

Enzymic lipid peroxidation in the microsomal fraction of rat brain

Abstract: An enzymic lipid peroxidation system has been demonstrated in the microsomal fraction of rat brain and the requirements and optimal conditions for assay determined. The involvement of NADPH-cytochrome c reductase was demonstrated in vesicles reconstituted with lipids extracted from the brain microsomal fraction. Further characterization of the system made use of substances shown to inhibit the liver microsomal system. α-Tocopherol was shown to be an effective inhibitor of lipid peroxidation in the brain microsomal system, whereas Na₂SO₃ had no effect, which is indicative that free radical transfer occurs only in the hydrophobic regions. Neither superoxide dismutase nor catalase inhibited lipid peroxidation. The implications of an NADPH-cytochrome c reductase-dependent lipid peroxidation system that is not linked to a drug hydroxylation system and appears to differ from the liver microsomal system in a number of other ways are discussed.     

GA1处理采后油桃果实膜脂过氧化的影响

采后GA3处理“阿姆肯”油桃果实（Prunus Persica (L.)nectarine.cv.‘armking’),降低了果实中过氧化氢（H2O2）积累和膜脂过氧化产物丙二醛（MDA）含量,显著提高了活性氧清除酶过氧化氢酶（CAT）和抗氧化剂谷胱甘肽（GSH）的含量,降低了果实衰老期间的膜脂过氧化,对“阿姆肯”油桃有一定保鲜效果。     

Effects of iron-induced lipid peroxidation and of acidosis on choline uptake by synaptosomes

The effects of iron-induced lipid peroxidation and of lactic acidosis on [³H]choline uptake were investigated on crude synaptosomes prepared from rat cerebral cortices. Fe²⁺-induced lipid peroxidation as evidenced from the production of thiobarbituric acid reactives substances (TBARS) was correlated with a decrease in high-affinity choline uptake (HACU). Trolox C, a free radical scavenger, prevented both Fe²⁺-induced TBARS production and decrease in HACU. Lactic acidosis (pH 6.0 for 30 or 60 min) increased the TBARS production with concomitant decrease in HACU (–48%, –78%, respectively). The acidosis dependent decrease was not reversible following pH 7.4 readjustment after 60 min acidosis. It was not prevented by trolox C, although trolox C inhibited the acidosis-induced production of TBARS. The results suggest that the contribution of acidosis to peroxidative damages is probably of less importance in comparison to other cytotoxic mechanisms.     

Free fatty acids,lipid peroxidation,and lysosomal enzymes in experimental focal cerebral ischemia in primates: Loss of lysosomal latency by lipid peroxidation

Experimental focal cerebral ischemia was produced in monkeys (Macaca radiata) by occlusion of the right middle cerebral artery (MCA). The release of the lysosomal glycosidases, -d-hexosaminidase, -l-fucosidase and -d-mannosidase into the soluble fraction in the right basal ganglia of the experimental animals was measured at different periods from 30 min to 12 hr after occlusion and compared with the corresponding sham operated control animals. There was a significant increase in the released lysosomal enzymes in the MCA occluded animals at all periods and particularly at 4 hr after occlusion. The CSF from the experimental animals also showed elevated levels of hexosaminidase and fucosidase. The free fatty acids (FFA) measured in the basal ganglia at 30 min and 2 hr after occlusion showed a 100 fold increase in the experimental animals. The predominant fatty acid released was linoleic acid (18:2) followed by arachidonic acid (20:4). Lipid peroxidation in the basal ganglia measured by the thiobarbituric acid (TBA) reaction in the presence or absence of ascorbic acid also showed a significant increase in the experimental animals at all periods with a maximum at 30 min to 2 hr after occlusion. In order to assess whether lipid peroxidation causes damage to the lysosomes and release of the enzymes, a lysosome enriched P₂ fraction from the normal monkey basal ganglia was prepared and the effect of peroxidation studied. Maximum peroxidation in the P₂ fraction was observed in the presence of arachidonic acid, ascorbic acid and Fe²⁺. There was a good correlation between the extent of lipid peroxidation and the in vitro release of lysosomal hexosaminidase from the P₂ fraction. Anti-oxidants which strongly inhibited lipid peroxidation in the P₂ fraction prevented the release of hexosaminidase. The results suggested that in ischemia produced by MCA occlusion lipid peroxidation which damages the lysosomal membrane causes the release of lysosomal hydrolytic enzymes.Abbreviations used BHA butylated hydroxyanisole - BHT butylated hydroxytoluene - FFA free fatty acids - MCA middle cerebral artery - MDA malonaldehyde - PUFA polyunsaturated fatty acids - TBA thiobarbituric acid     

Effects of magnesium and iron on lipid peroxidation in cultured hepatocytes

In primary cultures of rat hepatocytes, the effects of extracellular Mg²⁺ and Fe on lipid peroxidation (LPO) as measured by means of malondialdehyde (MDA) formation were investigated.Incubation of hepatocytes at decreasing extracellular Mg²⁺ concentration enhanced LPO, depending on extracellular Fe. About 96% of MDA accumulated in the culture medium. Addition of desferrioxamine prevented LPO.Additionally, the formation of oxygen free radicals was determined by fluorescence reduction of cis-parinaric acid. With this method, an immediate decay of fluorescence was found after addition of Fe²⁺. Fluorescence reduction was completely prevented by desferrioxamine, indicating the function of extracellular Fe. This mechanism may operate additionally to the increase in intracellular Fe and intracellular formation of oxygen free radicals during Mg deficiencyin vivo.     

膜脂过氧化产物在光敏诱发细胞突变中的作用

本文选用ＣＨＯ细胞,通过竹红菌甲素（ＨＡ）光敏诱变及ｏｕａ选择性培养液的筛选,证实甲素光敏反应对细胞Ｎａ＾＋／Ｋ＾＋ ＡＴＰ酶基因具有诱变致突作用。对其突变效应与脂质过氧化反应及ＤＮＡ加成物形成关系的分析表明,ＴＢＡ反应产物随着光照时间的增加而增加,同时ＤＮＡ加成物生成迅速增加,突变频率也随之增高。维生素Ｅ可抑制脂质过氧化反应,并减少ＤＮＡ加成物生成,阻止细胞突变率的增加。提示光敏诱发细胞脂质过氧