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PubMed1993

Contraceptive steroids increase erythrocyte lipid peroxidation in female rats.

In order to investigate the effects of contraceptive steroid combinations on lipid peroxidation in the erythrocyte membranes, adult female rats were divided into 2 groups for short- and long-term investigations; each group was then subdivided into 5 subgroups according to orally given low and high doses of EE/NEA (ethinyl estradiol/norethisterone acetate) and EE/LNG (ethinyl estradiol/levonorgestrel) combinations and control group. Since EE was included in each combination, the groups were named according to the progestin (NEA, LNG) components. At the end of the experiment periods, lipid peroxidation in the erythrocyte membranes from rats was measured. When compared to the controls, except low-dose LNG groups, lipid peroxidation levels were increased in all study groups. It was seen that the effect of NEA and LNG combinations on lipid peroxidation was not time-, but dose-dependent. When these combinations were compared to each other, different effects of NEA and LNG on lipid peroxidation were not detected in the experiment period. As a result, the increased lipid peroxidation following the administration of contraceptive steroid combinations is a very important finding that should be taken into account, in addition to the effects of these steroids on lipid and lipoprotein metabolism.

Administration, Oral↗
PubMed1988

Effects of lipid peroxides on prostacyclin and thromboxane generation in hypercholesterolemic rabbits.

Rabbits fed an atherogenic diet for 60 days resulted in high levels of plasma lipid peroxides as well as extreme hypercholesterolemia. Both levels stayed high until 35 days after the atherogenic diet stopped. At the same time, plasma PGI2 level was remarkably decreased while TXA2 and platelet aggregability were increased. Atherosclerotic aortas contain high levels of lipid peroxides associated with decreased PGI2 and increased TXA2 generation. Atherosclerotic plaques had the highest level of lipid peroxides and TXA2 while PGI2 production was the least, as compared with nonplaque tissue of the same artery and the normal arteries. The condition of normal arteries was just the reverse. There was a negative correlation between lipid peroxides and prostacyclin production, and a positive correlation between lipid peroxides and TXA2, in both plasma and aorta of rabbits. These results suggest that there is a close correlation between atherosclerosis, elevated lipid peroxides, and disturbances in PGI2/TXA2 balances.

Animals↗
PubMed1983

Protection against lipid peroxidation by a microsomal glutathione-dependent labile factor.

Glutathione (GSH) protects rat liver microsomes against ascorbic acid (0.2 mM)/ferrous iron (10 microM)-induced lipid peroxidation for some time. The inhibitory effect of GSH is concentration-dependent (0.1-1.0 mM). Our data suggest that GSH acts by preventing initial radical formation rather than via radical scavenging or GSH--peroxidase activity. A labile GSH-dependent factor is involved in the inhibition of microsomal lipid peroxidation by GSH, inasmuch as heating the microsomes abolishes the GSH effect. We found that besides heating, lipid peroxidation also destroys the GSH-dependent factor. Consequently, continuous radical stress will produce lipid peroxidation, despite the presence of GSH. Moreover, a detrimental effect of in vivo-induced lipid peroxidation (CCl4-treatment) on the GSH-dependent factor was observed. The implications of the present data for the genesis of and the protection against peroxidative damage are discussed.

Animals↗
PubMed1986

Influence of lipid peroxidation on beta-adrenoceptors.

The peroxidation of lipids in biological membranes is a destructive phenomenon that can be elicited in various ways. Surface receptor molecules that allow cells to respond to hormones are possibly inactivated during lipid peroxidation. Effects of lipid peroxidation on receptors have not been extensively examined thus far. This investigation shows that there is a decrease in beta-adrenoceptor density (measured as specific (-)-[125I]iodocyanopindolol binding) during lipid peroxidation, in both lungs and erythrocytes of the rat. To this end, lung membranes (containing both beta 1- and beta 2-adrenoceptors) and intact erythrocytes (containing a homogeneous beta 2-adrenoceptor population) were pretreated with cumene hydroperoxide (lung membranes with 0.1 mM and erythrocytes with 1 mM) and Fe2+ (1 X 10(-5) M) for 60 min which resulted in extensive lipid peroxidation measured as malondialdehyde formation. The ration beta 1-:beta 2-adrenoceptor density in lung membranes after treatment with cumene hydroperoxide did not change and remained at 30%:70%. A single injection (i.p.) with the herbicide paraquat (50 mg/kg, 24 h), which is known to cause lung damage via lipid peroxidation, resulted in similar alterations in receptor density to those caused by cumene hydroperoxide in the in vitro experiments.

Animals↗
PubMed1985

Effects of pantethine on in-vitro peroxidation of low density lipoproteins.

The effects of pantethine on LDL peroxidation in vitro are reported. LDL isolation by density gradient ultracentrifugation from 12 normal subjects were dialyzed 48 h under conditions allowing oxidation. The LDL peroxides were assayed for the presence of malondialdehyde (MDA) on the lipoprotein. The effect of peroxidation on the LDL protein moiety (apo B) was studied by SDS-gel electrophoresis. The presence in the dialysis buffer of 1 mM reduced glutathione or of an equimolar concentration of pantethine markedly inhibited the MDA formation in LDL. Less effective were 0.5 and 2 mM pantethine, while 10 mM pantethine did not prevent the LDL peroxidation. Both glutathione and pantethine (1 or 2 mM) preserved the original LDL electrophoretic mobility. The electronegative charge of LDL was correlated to the MDA production during the dialysis procedures. Freshly prepared LDL showed a single apo B band by SDS-gel electrophoresis (apo B-100). Following peroxidation 2 or 3 bands with higher molecular weight appeared. Both glutathione and pantethine (1 or 2 mM) strongly inhibited the appearance of higher molecular weight peptides. In appropriate concentrations therefore pantethine inhibits the LDL peroxidation in vitro, thus preserving the molecular integrity of apo B.

Antioxidants↗
PubMed1992

Mutational spectra in human B-cells. Spontaneous, oxygen and hydrogen peroxide-induced mutations at the hprt gene.

To test the hypothesis that reactive species in the oxygen cascade are responsible for spontaneous mutation, we examined the spectra of oxygen and hydrogen peroxide-induced mutations at the hprt locus in a human B-lymphoblastoid cell line. We compared these spectra with the spontaneous mutational spectrum. Large gene alterations were studied by Southern analysis of individual TGR clones. A combination of high fidelity polymerase chain reaction, denaturing gradient gel electrophoresis and direct DNA sequencing were used to detect and identify point mutations in exon 3 of hprt. With regard to spontaneous mutations, a previous study showed that 39% of the spontaneous TGR clones had large gene alterations. In the present study, the analysis of spontaneous point mutations within exon 3 revealed two hotspots. A one base-pair deletion (-A) at base-pair 256 or 257 and a two base-pair deletion (-GG) at base-pair 237 and 238, were detected in triplicate cultures. Each of the hotspots comprised about 1% of the TGR mutants. The analysis of individual oxygen-induced TGR clones (48 h, 910 microM-O2) showed 43% had large gene alterations similar to the spontaneous TGR clones. However, none of the spontaneous point mutation hotspots was found among triplicate oxygen-treated cultures. Two point mutations in common with H2O2-treated cultures were found in one of the three oxygen-treated cultures. Hydrogen peroxide-induced mutations (1 h, 20 microM) also differed from spontaneous mutations. Only 24% of the hydrogen peroxide-induced TGR clones had large gene alterations. The analysis of point mutations showed three hotspots within exon 3 of hprt. An AT to TA transversion at base-pair 259 had an average frequency of 3% of all TGR mutants (present in all of 3 H2O2-treated cultures). Two GC to CG transversions at base-pairs 243 and 202 were present at a frequency of 0.6% and 0.4%, respectively. A five base-pair deletion (base-pair 274 to 278) was present at an average frequency of 0.3%. The latter three mutations were detected in two of three H2O2-treated cultures. Thus, the point mutation spectra of both oxygen and hydrogen peroxide were significantly different from the spontaneous spectrum. The oxygen and hydrogen peroxide-induced spectra shared some features, suggesting that oxygen and hydrogen peroxide share some but not all pathways for induction of mutations within the DNA sequence studied here.(ABSTRACT TRUNCATED AT 400 WORDS)

B-Lymphocytes↗
PubMed1988

Plasma thiobarbituric acid reactivity: reaction conditions and the role of iron, antioxidants and lipid peroxy radicals on the quantitation of plasma lipid peroxides.

The effects of Fe3+, lipid peroxy radicals and the antioxidant butylated hydroxytoluene on the 2-thiobarbituric (TBA) acid quantitation of plasma lipid peroxides were investigated. Whole plasma and plasma fractions prepared by trichloroacetic acid (TCA) protein precipitation and lipid extraction, demonstrated markedly differing TBA reactivities in the presence or absence of added Fe3+. Examination of the spectral profiles of the TBA reacted whole plasma and TCA precipitated fractions demonstrated the presence of interfering compounds which gave rise to an artifactual increase in lipid peroxide concentrations. In contrast the TBA reacted lipid extracts had low levels of interfering compounds that could be removed by our previously described high pressure liquid chromatographic method (Wade, Jackson and van Rij (1985) Biochem. Med. 33, 291-296). Further characterization of the TBA reactivity of the lipid extract showed that Fe3+ at an optimal concentration of 0.5 mM was necessary for the quantitative decomposition of the lipid peroxides to the TBA reactive product malondialdehyde (MDA). However the presence of Fe3+ resulted in further peroxidation of any unsaturated lipids present. Butylated hydroxytoluene (BHT) at an optimal concentration of 1.4 mM inhibited Fe3+ stimulated peroxidation without affecting the formation of the MDA-TBA chromogen. Using a standardized TBA test with plasma lipid extracts and the addition of optimal concentrations of Fe3+ and BHT, we have determined the mean concentration of lipid peroxides in 30 healthy human subjects to be 102.7 +/- 20.0 ngm/ml.

Butylated Hydroxytoluene↗
PubMed1988

Ferriprotoporphyrin IX and cell lysis: a protective role for hydrogen peroxide.

Two potentially lytic substances, ferriprotoporphyrin IX (FP) and hydrogen peroxide, may coexist and partially detoxify each other in sickle cells and in erythrocytes infected with malaria parasites. Since hydrogen peroxide can decompose FP, its effect on hemolysis induced by FP and by the complex of FP with chloroquine was investigated. Human erythrocytes suspended at a concentration of 0.5% in a 50 microM solution of FP underwent approximately 42% hemolysis during the course of 2 hours. Twenty-five micromolar chloroquine potentiated hemolysis to 99%, and preincubation of 50 microM FP with 25 microM hydrogen peroxide for 5 minutes reduced hemolysis to 4%. Mixing either FP or hydrogen peroxide first with chloroquine abolished the effect of hydrogen peroxide. Detoxification of FP by hydrogen peroxide may be an important protective mechanism in certain hemolytic anemias, and inhibition of detoxification could account for the effectiveness of chloroquine in malaria.

Chloroquine↗
PubMed1985

Mutation induction in Escherichia coli incubated in the reaction mixture of NADPH-dependent lipid peroxidation of rat-liver microsomes.

Experiments were carried out to examine mutation induction in E. coli cells incubated in the reaction mixture of NADPH-dependent lipid peroxidation of microsomes isolated from rat liver. The results obtained were as follows: (1) Lipid peroxidation of microsomes occurred extensively on incubation with NADPH and Fe2+. In the E. coli WP2uvrA(pKM101) system, the mutation frequency to streptomycin resistance increased markedly when the cells were incubated in the reaction mixture of microsomal lipid peroxidation. The induced mutation frequencies were dependent on the extent of the lipid peroxidation. (2) It was also found that the mutations were induced at the same rate as in the case of (1) when the cells were added to the microsomal suspensions after the reactions due to the short-lived free radicals had terminated. (3) The cytotoxicity of the lipid peroxidation products was larger in the DNA repair-defective mutant, E. coli SR18 (uvrArecA) than the wild-type strain, SR749. From these results it is concluded that some DNA-damaging and mutagenic substances are indeed produced in the degradation process of peroxidized polyunsaturated fatty acids in liver microsomal lipids.

Animals↗
PubMed1993

Thioridazine induces lipid peroxidation in myelin of rat brain.

In this study, the oxidative effect of the commonly used phenothiazine, thioridazine, on brain tissue has been investigated. Thioridazine (0.1 and 0.5%) supplemented in pellet diet (w/w), produced a significant increase (P < 0.001) in levels of myelin lipid peroxide, after 3 weeks of treatment. Besides myelin, there was a 2-fold increase in the mitochondrial lipid peroxides, as a result of treatment with thioridazine. However, these elevated levels of lipid peroxides returned to normal after withdrawal of thioridazine for 2 weeks. Myelin-associated enzyme activities of Na+,K(+)-ATPase and 5'-nucleotidase became inhibited by 20-25%, but CNPase activity was unaffected. Studies of in vitro lipid peroxidation on purified myelin from untreated rats suggested that extensive lipid peroxidation of myelin in thioridazine-treated rats could underlie inhibition of the myelin enzymes. Morphological studies revealed little or no structural alterations in myelin, produced by thioridazine. These studies suggest that thioridazine induces a reversible lipid peroxidation in myelin, that could result in functional alterations of the myelin-associated enzymes, during use of this drug.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1993

Catalase protection against hydrogen peroxide-induced injury in rat oral mucosa.

Hydrogen peroxide in contact with the oral mucosa induces vesicle formation and ulceration. This study assesses the protective effect of catalase against the hydrogen peroxide insult in the rat tongue mucosa. In addition, we report a detailed histologic characterization of the mucosal injury. Four repetitive applications of 30% hydrogen peroxide at 15 minute intervals produced a vast edema of the submucosal tissue including the tongue muscles that was seen immediately after the last application. Histomorphometric measurements indicated a substantial regression of the edema 1 day later with the appearance of a very large ulceration lined by a pyogenic membrane. Animals examined 7 days after the hydrogen peroxide administration revealed almost complete healing in terms of absence of edema and renewal of intact epithelial lining. Catalase applied to the tongue before the hydrogen peroxide fully prevented the pathologic tissue reaction. Thus testing of the clinical feasibility of catalase in protecting the oral mucosa against hydrogen peroxide-induced injury is strongly indicated.

Animals↗
PubMed1984

Studies on the biochemical effects of nitrogen dioxide. IV. Relation between the change of lipid peroxidation and the antioxidative protective system in rat lungs upon life span exposure to low levels of NO2.

This study examined the relation between lipid peroxidation and the antioxidative protective system in lungs of rats exposed to low levels of nitrogen dioxide (NO2). JCL:male Wistar rats were exposed to 0, 0.04, 0.4, and 4 ppm NO2 for 9, 18, and 27 months. Lipid peroxidation measured by TBA method, increased significantly in the 4 ppm NO2 group of the 9-month exposure and in the 0.4 and 4 ppm NO2 groups of the 18-month exposure. The activity of glutathione peroxidase measured with hydrogen peroxide as substrate decreased significantly in the 4 ppm NO2 group of the 9-month exposure and in the 0.4 and 4 ppm NO2 groups of the 18-month exposure. Furthermore, the activities of two glutathione S-transferases, aryl and aralkyl S-transferase, also decreased in the 0.4 and 4 ppm NO2 groups of the 18-month exposure, but not in any groups of the 9-month exposure. The activity of glutathione peroxidase measured with cumene hydroperoxide as substrate did not show any significant changes in any NO2 group. The activities of glucose-6-phosphate dehydrogenase and glutathione reductase were significantly higher than those in the control group for the 9-month exposure. In the 18-month exposure, however, they showed a tendency to return to control level. The activities of superoxide dismutase and disulfide reductase upon NO2 exposure for 9 and 18 months were not different from control values. To confirm that lipid peroxidation was increased with greater NO2 concentrations and exposure times, ethane and pentane exhalation in breath as an index of lipid peroxidation was examined. Ethane exhalation increased significantly following 0.04, 0.4, and 4 ppm NO2 exposure for 9 and 18 months. Furthermore, ethane formation of rats exposed to 0.04 and 0.4 ppm NO2 for 27 months also increased to twice the control level. On the other hand, after exposure to 4 ppm NO2 for 27 months, ethane levels returned to control level. Pentane formation increased significantly only in the 0.04 and 0.4 ppm groups in the 18-month exposure. Ethane exhalation in rats exposed to 0.04, 0.12, and 0.4 ppm NO2 for 9 and 18 months was similar. These results suggested that the antioxidative protective ability was decreased with prolonged exposure, while formation of cytotoxic lipid peroxides was increased.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Inhibition of doxorubicin-initiated membrane damage by N-acetylcysteine: possible mediation by a thiol-dependent, cytosolic inhibitor of lipid peroxidation.

Peroxidative damages are thought to be a component of doxorubicin-induced cardiac toxicity. Administration of certain thiols, such as N-acetylcysteine, are reported to be protective against the cardiac toxicity and mortality associated with chronic doxorubicin administration. We have investigated the possibility that N-acetylcysteine exerts its protective effect by inhibiting doxorubicin-induced lipid peroxidation in a process mediated by a heat-labile cytosolic factor. Dialyzed rat liver cytosol plus N-acetylcysteine significantly inhibited doxorubicin-induced lipid peroxidation in a microsomal system whereas neither cytosol nor N-acetylcysteine alone does so. Concomitantly, it was observed that N-acetylcysteine is rapidly consumed in a system containing cytosol, microsomes, and doxorubicin. The inhibition of lipid peroxidation by the cytosol and accompanying N-acetylcysteine oxidation is heat labile. Rat heart cytosol showed a similar N-acetylcysteine-dependent inhibition of doxorubicin-induced lipid peroxidation, but heart cytosol was less potent than hepatic cytosol on the basis of protein content. The antioxidant property of heart cytosol as well as its capacity to oxidize N-acetylcysteine was inhibited by prior treatment of the cytosol with iodoacetic acid. This suggested that the factor possessed essential sulfhydryl groups. These results suggest that hepatic and cardiac cytosols contain heat-labile components capable of utilizing N-acetylcysteine as a substrate to suppress the doxorubicin-induced peroxidative damage to microsomes induced by doxorubicin. These components may play a role in the protective effects of N-acetylcysteine against doxorubicin-induced cardiac toxicity and mortality.

Acetylcysteine↗
PubMed1989

Halomethane hepatotoxicity: induction of lipid peroxidation and inactivation of cytochrome P-450 in rat liver microsomes under low oxygen partial pressures.

Halomethane-induced lipid peroxidation and inactivation of cytochrome P-450 were studied in liver microsomes from phenobarbital-pretreated rats in the presence of NADPH at steady-state O2 partial pressures (PO2). As indicated by the formation of thiobarbituric acid-reactive material and the stimulation of O2 uptake, significant lipid peroxidation was induced by those halomethanes containing more than two Cl, Br, or I atoms. Lipid peroxidation decisively depended on the PO2 present, showing distinct maxima at PO2 between 1 and 10 mm Hg. Those halomethanes inducing lipid peroxidation also led to inactivation of microsomal cytochrome P-450, as indicated by a loss of cytochrome P-450 detectable as ferrous CO complex and an equimolar loss of microsomal heme. Under anaerobic conditions inactivation of cytochrome P-450 presumably resulted solely from an attack of halomethane radicals on its heme moiety. Under aerobic conditions lipid peroxidation made an additional contribution to the inactivation of cytochrome P-450. These results suggest that the reductive activation to free radicals, catalyzed by cytochrome P-450, and thus the induction of lipid peroxidation at low but physiological PO2 are characteristic not only of CCl4 but also of other polyhalogenated methanes, especially CBrCl3, CBr4, CHI3, CHBr3, and CHBr2Cl.

Animals↗
PubMed1982

Role of peroxidation in erythrocyte aging.

The role of membrane peroxidation in red cell aging was investigated by exposing rat erythrocytes to a peroxide-generating system of xanthine oxidase with hypoxanthine, and the resulting alterations were compared to those observed during in vivo aging. Erythrocyte incubation with peroxides decreased the activities of adenylate cyclase and protein kinase, enzymes which were found to be reliable markers reflecting differences between young and old cells. Membranes from age-separated erythrocytes were solubilized and subjected to electrophoresis on gradient polyacrylamide-sodium dodecyl sulfate gels. Electrophoretic patterns indicated that old erythrocytes contained higher amounts of several membrane proteins than young cells. These were proteins in bands 2.1 and 4.1, and proteins of molecular weight larger than 250,000. There was a relative increase in the amount of proteins in band 4.1 and the high molecular weight (greater than 250,000) proteins as a results of peroxidation. These studies demonstrate that cells incubated in vitro with a peroxide-generating system resemble senescent erythrocytes in membrane enzyme activities, cell density, and membrane protein composition. We propose that peroxidation plays an important role in red cell aging.

Adenylyl Cyclases↗
PubMed1985

Inhibition of antithrombin III by lipid peroxides.

A study was made of the inhibition of antithrombin III (At III) activity by lipid peroxides prepared from autoxidation of unsaturated fatty acids. Lipid peroxides markedly reduced the thrombin neutralising activity of plasma and purified At III with or without albumin carrier. Heparin Sepharose chromatography and heparin cofactor assays suggested that the primary target of lipid peroxides on the At III molecule may be the heparin binding site. Results from electrophoretic studies suggested that interaction between lipid peroxides and At III increased the negative charge of the At III molecule; however, no aggregation of the At III molecule was observed. Lipid peroxidation is being increasingly recognised as a factor in the pathogenesis of several disease states, and it is possible that local inhibition of At III by lipid peroxides could contribute towards the development of a thrombotic event.

Antithrombin III↗
PubMed1981

Serum lipoproteins, lipid peroxides and prostacyclin biosynthesis in patients with coronary heart disease.

Serum low-density lipoproteins (LDL) and high-density lipoproteins (HDL) were prepared by gradient ultracentrifugation and dialysis from 12 healthy subjects and 15 patients with coronary heart disease and hyperlipoproteinemia. In both lipoprotein fractions cholesterol and lipid peroxides were determined. The effect of these lipoproteins on spontaneous prostacyclin biosynthesis in rat aortic slices was studied. Serum lipoproteins were susceptible to peroxidation during the preparation procedure. LDL were more prone to peroxidation than HDL. Little lipid peroxides were formed in lipoproteins when calcium ions had been removed by EDTA, and when butylated hydroxytoluene (BHT) was present at all stages of their preparation. LDL when prepared without these precautions either from healthy subjects or from patients with coronary heart disease markedly suppressed prostacyclin generation by rat aortic slices. This inhibition was unrelated to LDL-cholesterol, but was due to LDL-lipid peroxides. Peroxide-low LDL prepared from most of the healthy subjects and patients with coronary heart disease and concomitant hyperlipoproteinemia, did not inhibit prostacyclin biosynthesis. However, in one quarter of the patients, LDL was inhibitory. Consequently, in some patients with coronary heart disease, there operate unknown mechanisms which are responsible for the inhibitory activity of LDL on prostacyclin generation.

Adult↗
PubMed1983

Inhibition of prostaglandin I2 (PGI2) formation by LDL-cholesterol or LDL-peroxides?

A hypothesis of Gryglewski et al. explains the correlation between increased level of LDL and development of atherosclerosis by inhibition of PGI2 synthesis by increased peroxide content of LDL. The aim of the present paper was to examine this hypothesis. The major results are: 1) Preparation of LDL in the presence of .02% butylated hydroxytoluene did not reduce the lipid peroxide content of LDL from men and women and not change the inhibition or stimulation of the in vitro biosynthesis of PGI2 by LDL isolated from blood of men or women, respectively. 2) In the LDL and HDL, respectively, of healthy men we found nearly the same lipid peroxide levels (nmole malondialdehyde (MDA)/mg lipoprotein-cholesterol) as in the lipoproteins of male patients with hyperlipidemia type IIa or IV, but the peroxide concentration is three times higher in HDL as in LDL. 3) LDL isolated from healthy men inhibited in dose dependent fashion the generation of PGI2 from PGH2 by aortic microsomes whereas LDL from premenopausal women stimulated PGI2 formation even calculated as LDL lipid peroxides (in nM MDA/ml). The results call into question the hypothesis that diminished PGI2 formation by atherosclerotic vessels is related to inhibition of PGI2 synthetase by lipid peroxides present in LDL in the lesions. A new working hypothesis is presented that also the fatty acid pattern and the lipid class composition in the LDL are important for their influence on the PGI2 formation.

Animals↗