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At least 19 recordsLinked to original sources
PubMed1995

Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. Smoking as a cause of oxidative damage.

BACKGROUND: It has been hypothesized that the pathogenesis of diseases induced by cigarette smoking involves oxidative damage by free radicals. However, definitive evidence that smoking causes the oxidative modification of target molecules in vivo is lacking. We conducted a study to determine whether the production of F2-isoprostanes, which are novel products of lipid peroxidation, is enhanced in persons who smoke. METHODS: We measured the levels of free F2-isoprostanes in plasma, the levels of F2-isoprostanes esterified to plasma lipids, and the urinary excretion of metabolites of F2-isoprostanes in 10 smokers and 10 nonsmokers matched for age and sex. The short-term effects of smoking (three cigarettes smoked over 30 minutes) and the effects of two weeks of abstinence from smoking on levels of F2-isoprostanes in the circulation were also determined in the smokers. RESULTS: Plasma levels of free and esterified F2-isoprostanes were significantly higher in the smokers (242 +/- 147 and 574 +/- 217 pmol per liter, respectively) than in the nonsmokers (103 +/- 19 and 345 +/- 65 pmol per liter; P = 0.02 for free F2-isoprostanes and P = 0.03 for esterified F2-isoprostanes). Smoking had no short-term effects on the circulating levels of F2-isoprostanes. However, the levels of free and esterified F2-isoprostanes fell significantly after two weeks of abstinence from smoking (250 +/- 156 and 624 +/- 214 pmol per liter, respectively, before the cessation of smoking, as compared with 156 +/- 67 and 469 +/- 108 pmol per liter after two weeks' cessation; P = 0.03 for free F2-isoprostanes and P = 0.02 for esterified F2-isoprostanes). CONCLUSIONS: The increased levels of F2-isoprostanes in the circulation of persons who smoke support the hypothesis that smoking can cause the oxidative modification of important biologic molecules in vivo.

Adult↗
PubMed1995

Excretion of F2-isoprostanes in bile: a novel index of hepatic lipid peroxidation.

Lipid peroxidation is believed to be an important mechanism of liver injury caused by some xenobiotics. However, it has been difficult to demonstrate and quantify this process in vivo. Moreover, little is known about the disposition of lipids oxidized in the liver. F2-isoprostanes are prostanoids produced by nonenzymatic free radical-catalyzed peroxidation of arachidonic acid esterified to phospholipids. Hydrolysis of F2-isoprostanes from phospholipids by phospholipases yields free F2-isoprostanes. Excretion of F2-isoprostanes, both free and esterified to phospholipids, was measured in bile after administration of CCl4. The concentration of lipid-esterified F2-isoprostanes in bile exceeded that of free F2-isoprostanes. CCl4 caused a dose-dependent increase in biliary F2-isoprostane excretion that correlated better with the increase in liver F2-isoprostanes than it did with the increase in plasma F2-isoprostanes. Pretreatment with colchicine ameliorated CCl4-liver injury but did not affect baseline or CCl4-induced biliary F2-isoprostane excretion. Administration of diquat to selenium-deficient rats, which causes hepatic and renal necrosis, was associated with a 13-fold elevation of plasma F2-isoprostanes. However, both hepatic F2-isoprostane concentrations and biliary F2-isoprostane excretion were increased only threefold. These data suggest that quantification of F2-isoprostane excretion in bile may provide a sensitive and quantitative index of hepatic lipid peroxidation.

Animals↗
PubMed1995

Formation of F2-isoprostanes during oxidation of human low-density lipoprotein and plasma by peroxynitrite.

F2-Isoprostanes are novel bioactive prostaglandin F2-like compounds produced by nonenzymatic free radical-catalyzed peroxidation of arachidonic acid. F2-Isoprostanes are initially formed in situ on phospholipids and subsequently released. Quantification of the F2-isoprostanes has been found to represent a valuable and reliable marker of lipid peroxidation. Oxidative modification of low-density lipoprotein (LDL) is a key process for the recognition of LDL by the scavenger receptors on macrophages. The oxidative mechanism responsible for the modification of LDL in vivo remains unclear, but an attractive candidate is the powerful oxidant peroxynitrite, which can be formed by reaction of nitric oxide and superoxide in the vessel wall. To further explore the potential role of peroxynitrite in the oxidative modification of plasma lipids, we investigated whether incubation of LDL and plasma with peroxynitrite or SIN-1, which decomposes to form nitric oxide and superoxide, catalyzes the formation of F2-isoprostanes. Incubation of LDL with peroxynitrite (0.125 to 1 mmol/L) or SIN-1 (0.5 and 1 mmol/L) induced a concentration-dependent increase in the formation of F2-isoprostanes, reaching a maximum of 5.5 +/- 2.05-fold (SEM) and 18.2 +/- 4.0-fold above control values, respectively. The increase of F2-isoprostanes induced by SIN-1 was essentially completely inhibited by superoxide dismutase. Incubation of plasma with peroxynitrite or SIN-1 yielded similar results. These results indicate that peroxynitrite can induce the formation of F2-isoprostanes in lipoproteins. Since F2-isoprostanes can exert potent biological activity such as vasoconstriction, they may contribute to the vascular pathobiology associated with atherosclerosis.

Antihypertensive Agents↗
PubMed1992

Formation of novel non-cyclooxygenase-derived prostanoids (F2-isoprostanes) in carbon tetrachloride hepatotoxicity. An animal model of lipid peroxidation.

These studies examine the in vivo formation of a unique series of PGF2-like compounds (F2-isoprostanes) derived from free radical-catalyzed nonenzymatic peroxidation of arachidonic acid. We have previously shown that levels of these compounds increase up to 50-fold in rats administered CCl4. To understand further the formation of these compounds in vivo, we carried out a series of experiments assessing factors influencing their generation. After CCl4 (2 ml/kg) was administered to rats, plasma F2-isoprostanes increased 55-fold by 4 h. Levels declined thereafter, but at 24 h, they were still elevated 21-fold, indicating continued lipid peroxidation. Pretreatment of rats with isonicotinic acid hydrazide and phenobarbital to induce cytochrome P-450 enhanced the production of F2-isoprostanes after CCl4 administration eightfold and fivefold, respectively, whereas inhibition of the cytochrome P-450 system with SKF-525A and 4-methylpyrazole decreased formation of F2-isoprostanes after CCl4 by 55 and 82%, respectively. Further, the glutathione-depleting agents buthionine sulfoximine and phorone augmented the F2-isoprostane response to CCl4 by 22- and 11-fold, respectively. F2-isoprostanes are formed in situ esterified to lipids and, in addition to increases in levels of free F2-isoprostanes in the circulation, levels of F2-isoprostanes esterified to lipids in various organs and plasma also increase sharply during CCl4 poisoning. The measurement of F2-isoprostanes may facilitate investigation of the role of lipid peroxidation in human diseases.

Acetaminophen↗
PubMed1992

Non-cyclooxygenase-derived prostanoids (F2-isoprostanes) are formed in situ on phospholipids.

We recently reported the discovery of a series of bioactive prostaglandin F2-like compounds (F2-isoprostanes) that are produced in vivo by free radical-catalyzed peroxidation of arachidonic acid independent of the cyclooxygenase enzyme. Inasmuch as phospholipids readily undergo peroxidation, we examined the possibility that F2-isoprostanes may be formed in situ on phospholipids. Initial support for this hypothesis was obtained by the finding that levels of free F2-isoprostanes measured after hydrolysis of lipids extracted from livers of rats treated with CCl4 to induce lipid peroxidation were more than 100-fold higher than levels in untreated animals. Further, increased levels of lipid-associated F2-isoprostanes in livers of CCl4-treated rats preceded the appearance of free compounds in the circulation, suggesting that the free compounds arose from hydrolysis of peroxidized lipids. This concept was supported by demonstrating that free F2-isoprostanes were released after incubation of lipid extracts with bee venom phospholipase A2 in vitro. When these lipid extracts were analyzed by HPLC, fractions that yielded large quantities of free F2-isoprostanes after hydrolysis eluted at a much more polar retention volume than nonoxidized phosphatidylcholine. Analysis of these polar lipids by fast atom bombardment mass spectrometry established that they were F2-isoprostane-containing species of phosphatidylcholine. Thus, unlike cyclooxygenase-derived prostanoids, F2-isoprostanes are initially formed in situ on phospholipids, from which they are subsequently released preformed, presumably by phospholipases. Molecular modeling of F2-isoprostane-containing phospholipids reveals them to be remarkably distorted molecules. Thus, the formation of these phospholipid species in lipid bilayers may contribute in an important way to alterations in fluidity and integrity of cellular membranes, well-known sequelae of oxidant injury.

Animals↗
PubMed1995

Analysis of F2-isoprostanes as indicators of non-enzymatic lipid peroxidation in vivo by gas chromatography-mass spectrometry: development of a solid-phase extraction procedure.

Recently, it has been reported that a series of prostaglandin F2-like compounds (F2-isoprostanes) are produced in vivo during peroxidation of arachidonic acid by a mechanism independent of the cyclooxygenase pathway. Of these, 8-epi-PGF2 alpha is shown to be a potent vasoconstrictor. We describe an improved method for analysing F2-isoprostanes in biological fluids. The method involves solid-phase extraction on an octadecylsilane (C18) and an aminopropyl (NH2) cartridge. After conversion to pentafluorobenzyl ester and trimethylsilyl ether derivatives, F2-isoprostanes are analysed by negative-ion chemical ionization mass spectrometry using tetradeuterated PGF2 alpha as the internal standard. The limit of detection of the assay was 10 pg/ml, with a coefficient of variation ranging from 9.4 to 15.1%. Analysis of plasma samples from healthy volunteers (n = 7) revealed no quantifiable levels of free (unesterified) 8-epi-PGF 2 alpha. However, the plasma samples contained 58 to 166 pg/ml of 8-epi-PGF2 alpha when analyzed for the total (sum of free and esterified) F2-isoprostanes. The main advantages of the method lie in the improved recovery, gas chromatographic separation and speed compared to existing techniques.

Deuterium↗
PubMed2026

Comparative evaluation of oxidative stress biomarkers F2-isoprostanes and 8-OHdG in Parkinson's disease and Type 2 Diabetes Mellitus: a systematic review and meta-analysis of human studies.

BACKGROUND: Oxidative stress is central to type 2 diabetes mellitus (T2DM) and Parkinson's disease (PD). However, the utility of biomarkers for lipid peroxidation (F2-isoprostanes) and DNA damage (8-OHdG) in the comorbidity of PD and T2DM remains unclear. METHODS: We conducted a systematic review and meta-analysis of 54 unique studies of human subjects aged &#x2265; 50&#x2009;years (n&#x2009;=&#x2009;7,521: 3,522 with T2DM, 722 with PD, and 3,277 controls), measuring biomarkers in serum, plasma, or leukocytes. Mixed-effects models quantified standardized differences (Hedges' g) across subgroups. RESULTS: In T2DM, F2-isoprostanes (g&#x2009;=&#x2009;1.60, 95% CI: 0.95-2.25) and 8-OHdG (g&#x2009;=&#x2009;2.64, 95% CI: 2.13-3.14) were markedly elevated (p&#x2009;<&#x2009;0.001). Stronger effects were observed in younger cohorts and serum/plasma samples, with complications like nephropathy exhibiting extreme oxidative stress (g&#x2009;=&#x2009;5.24). In PD, 8-OHdG was moderately elevated (g&#x2009;=&#x2009;0.78, 95% CI: 0.18-1.39; p&#x2009;=&#x2009;0.011), particularly in randomized controlled trials and plasma samples, whereas F2-isoprostanes were not significantly elevated (g&#x2009;=&#x2009;0.47, 95% CI: -0.43-1.38). High heterogeneity in T2DM (I2 > 90%) reflected methodological variability. CONCLUSION: Distinct profiles - both markers elevated in T2DM but only 8-OHdG in PD - underscore 8-OHdG's potential in PD-T2DM comorbidity. Future research should focus on standardized assays, multi-compartmental or multi-modal sampling, and longitudinal studies to clarify mechanisms and therapeutic targets.

Humans↗
PubMed1995

Formation of F2-isoprostanes in oxidized low density lipoprotein: inhibitory effect of hydroxytyrosol.

Oxidatively-modified low-density lipoproteins (LDL) contribute to the onset of the atherosclerotic disease. A recently discovered marker of lipid peroxidation in a series of prostaglandin F2-like compounds, the prostaglandin isomers isoprostanes, that are generated from arachidonic acid through cyclooxygenase-independent pathways following free radical injury and are endowed with potent biological activities. The incidence of cardiovascular disease in the Mediterranean area is low, possibly because of the type of fat (mainly olive oil) and other components (e.g. fruits and vegetables) of the diet. Natural antioxidants abound in this kind of diet and may also contribute to the observed protection from coronary heart disease (CHD) by retarding the formation of the atherosclerotic plaque. Olive oil, the major dietary fat in the Mediterranean countries, is rich in phenols with antioxidant properties. We thus investigated the formation of isoprostanes during in vitro LDL oxidation and tested the effect of an olive-oil-extracted phenol (i.e. hydroxytyrosol). Our data show that production of isoprostanes and other markers of lipid peroxidation occurs during LDL oxidation and is inhibited by hydroxytyrosol.

Antioxidants↗
PubMed1994

Isoprostanes. Novel markers of endogenous lipid peroxidation and potential mediators of oxidant injury.

It was recently discovered that a series of structurally unique prostaglandin F2-like compounds (F2-isoprostanes) capable of exerting potent biological activity are produced in vivo in humans by a noncyclooxygenase mechanism involving free radical catalyzed peroxidation of arachidonic acid. Considerable evidence has been obtained suggesting that quantification of F2-isoprostanes represents an important advance in our ability to assess oxidant status in vivo in humans. This has allowed us to implicate oxidant stress in the pathogenesis of human disease-for example, the hepatorenal syndrome. In addition to the F2-isoprostanes, we recently discovered that E-ring and D-ring isoprostanes are also produced in abundance in vivo by rearrangement of the isoprostane endoperoxide intermediates. We have also been able to demonstrate that one of the E2-isoprostanes, 8-epi-PGE2, is a potent renal vasoconstrictor in the rat. Insights into factors that may influence the formation of E2/D2-isoprostanes relative to F2-isoprostanes should be important in advancing our understanding of the biological consequences of the formation of isoprostanes in vivo.

Animals↗
PubMed2026

Association between sirtuin 1 and markers of oxidative stress in master athletes.

BACKGROUND: Lifelong training in master athletes confers protective effects, promoting higher sirtuin levels and enhanced antioxidant capacity. Although Sirtuin 1 (SIRT1) is well studied, no previous study has examined the relationship between circulating SIRT1 levels and antioxidant defense variables in master athletes. PURPOSE: To compare and analyze the relationships between circulating levels of SIRT1 and variables related to antioxidant defense in master athletes (MA) and untrained middle-aged individuals (UMA). METHODS: Male MA (n&#x2009;=&#x2009;42; 51.62&#x2009;&#xb1;&#x2009;7.33 years; &#x2265;10 years of training and competition in running) and UMA (n&#x2009;=&#x2009;15; 47.73&#x2009;&#xb1;&#x2009;8.52 years) were evaluated. Venous blood samples were collected for biochemical analyses of SIRT1, antioxidant enzymes, TBARS and F2-isoprostanes, 8-OHdG, and redox balance indexes. RESULTS: MA showed higher levels of SIRT1 (18.22&#x2009;&#xb1;&#x2009;4.53 vs. 6.08&#x2009;&#xb1;&#x2009;2.11 ng/mL; p&#x2009;<&#x2009;0.0001), as well as of SOD, CAT, and GSH (p&#x2009;<&#x2009;0.001), indicating a more favorable antioxidant profile. After adjustment for body fat percentage, differences in SOD, CAT, GSH and TBARS, remained significant. SIRT1 was positively correlated with SOD (r&#x2009;=&#x2009;0.279; p&#x2009;=&#x2009;0.031), CAT (r&#x2009;=&#x2009;0.485; p&#x2009;<&#x2009;0.001), GSH (r&#x2009;=&#x2009;0.476; p&#x2009;<&#x2009;0.001) and CAT/8-OHdG (r&#x2009;=&#x2009;0.430; p&#x2009;=&#x2009;0.032), and negatively correlated with TBARS (r&#x2009;=&#x2009;-&#x2009;0.518; p&#x2009;<&#x2009;0.001). CONCLUSION: Master athletes exhibited higher circulating SIRT1 concentrations and a more favorable systemic redox profile than untrained individuals, with SIRT1 being associated with markers of antioxidant defense, lipid peroxidation, and redox balance.

Aging↗
PubMed1994

Tirilazad mesylate protects stored erythrocytes against osmotic fragility.

The hypoosmotic lysis curve of freshly collected human erythrocytes is consistent with a single Gaussian error function with a mean of 46.5 +/- 0.25 mM NaCl and a standard deviation of 5.0 +/- 0.4 mM NaCl. After extended storage of RBCs under standard blood bank conditions the lysis curve conforms to the sum of two error functions instead of a possible shift in the mean and a broadening of a single error function. Thus, two distinct sub-populations with different fragilities are present instead of a single, broadly distributed population. One population is identical to the freshly collected erythrocytes, whereas the other population consists of osmotically fragile cells. The rate of generation of the new, osmotically fragile, population of cells was used to probe the hypothesis that lipid peroxidation is responsible for the induction of membrane fragility. If it is so, then the antioxidant, tirilazad mesylate (U-74,006f), should protect against this degradation of stored erythrocytes. We found that tirilazad mesylate, at 17 microM (1.5 mol% with respect to membrane lecithin), retards significantly the formation of the osmotically fragile RBCs. Concomitantly, the concentration of free hemoglobin which accumulates during storage is markedly reduced by the drug. Since the presence of the drug also decreases the amount of F2-isoprostanes formed during the storage period, an antioxidant mechanism must be operative. These results demonstrate that tirilazad mesylate significantly decreases the number of fragile erythrocytes formed during storage in the blood bank.

Antioxidants↗
PubMed1992

The F2-isoprostane, 8-epi-prostaglandin F2 alpha, a potent agonist of the vascular thromboxane/endoperoxide receptor, is a platelet thromboxane/endoperoxide receptor antagonist.

F2-isoprostanes are a recently discovered series of prostaglandin (PG)F2-like compounds that are produced in vivo in humans by nonenzymatic free radical catalyzed peroxidation of arachidonic acid. One of the compounds that can be produced in abundance by this mechanism is 8-epi-PGF2 alpha. 8-epi-PGF2 alpha is a potent vasoconstrictor in the rat, an effect that has been shown to be mediated via interaction with vascular thromboxane (TxA2)/endoperoxide (PGH2) receptors. In an effort to further understand the biological properties of this prostanoid in relation to its ability to interact with TxA2/PGH2 receptors, we examined its effects on human and rat platelets. At concentrations of 10(-6) M and 10(-5) M, 8-epi-PGF2 alpha induced only a shape change in human platelets and at higher concentrations (10(-4) M) induced reversible but not irreversible aggregation. Both the shape change and reversible aggregation were unaffected by indomethacin but were inhibited by the TxA2/PGH2 receptor antagonist SQ29548. Conversely, 8-epi-PGF2 alpha inhibited platelet aggregation induced by the TxA2/PGH2 receptor agonists U46619 (10(-6) M) and IBOP (3.3 x 10(-7) M) with an IC50 of 1.6 x 10(-6) M and 1.8 x 10(-6) M, respectively. 8-epi-PGF2 alpha also inhibited platelet aggregation induced by arachidonic acid. Similarly, in rat platelets, 8-epi-PGF2 alpha alone induced only modest reversible aggregation but completely inhibited U46619-induced aggregation.

Animals↗
PubMed1995

Immunological characterization of urinary 8-epi-prostaglandin F2 alpha excretion in man.

F2-isoprostanes are prostaglandin (PG) F2-like compounds that are formed in vivo directly by free radical-catalyzed lipid peroxidation. One of the compounds that can be produced in abundance by such mechanism is 8-epi-PGF2 alpha, a potent vasoconstrictor. We have developed an enzyme immunoassay and a radioimmunoassay for measuring urinary concentrations of 8-epi-PGF2 alpha by raising antibodies against this compound. The antisera presented high titers (> 1/300,000) and provided highly sensitive assays (IC50, 8 and 24 pg/ml, for EIA and RIA, respectively); cross-reactivity with other PG was negligible. The interassay reproducibility of EIA was assessed by measuring the same urine stored frozen in aliquots after solid phase extraction and thin-layer chromatography (17%, n = 13). Measurements of urinary 8-epi-PGF2 alpha by immunoassays were validated using different antisera and by comparison with gas chromatography/mass spectrometry. Healthy volunteers excreted 25 +/- 12 ng of 8-epi-PGF2 alpha/mmol creatinine (n = 19), with no circadian variation over three consecutive 8-hr collection periods (n = 10); preliminary results showed that excretion increased as a function of age. Urinary excretion of 8-epi-PGF2 alpha was unchanged by treatment with two nonsteroidal antiinflammatory drugs, Ibuprofen at 1.2 g/day for 4 days (n = 4) or aspirin as a single administration of 1 g (n = 6). In contrast, the urinary excretion of 11-dehydro-thromboxane B2, a platelet cyclooxygenase-derived metabolite was reduced by more than 80% after aspirin administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Formation of 8-iso-prostaglandin F2 alpha by human platelets.

F2-isoprostanes are free radical catalyzed prostaglandin F2 isomers formed from arachidonic acid in an enzyme independent manner (1). Analogous families of other prostaglandin isomers have also been described. Detection of these compounds in vivo has been postulated to represent an approach to the quantitative assessment of free radical generation in humans (2). Additionally, the 8-iso analogues of PGF2 alpha and PGE2 have been shown to induce vasoconstriction, a response which is prevented by pharmacological antagonists of the thromboxane receptor (3). Consequently, it is conceivable that these particular isomers might exhibit an autacoidal function. We chose to explore the factors which regulate the biosynthesis of one of these compounds, 8-iso-PGF2 alpha, in vivo and by human platelets in vitro, to understand more clearly how the discovery of these compounds might be exploited to further our understanding of free radical catalyzed processes in vivo.

Adult↗
PubMed1994

Role of nonenzymatically generated prostanoid, 8-iso-PGF2 alpha, in pulmonary oxygen toxicity.

Oxygen delivery at higher than ambient concentrations is in frequent clinical use, yet prolonged exposure can produce pulmonary edema in humans and animals. The specific mediators of oxygen toxicity are unknown, although evidence suggests that oxygen-based radicals such as superoxide anion contribute to this injury. Recently, 8-iso-prostaglandin F2 alpha (PGF2 alpha), an F2-isoprostane formed by free radical-initiated lipid peroxidation of arachidonic acid, has been implicated in pulmonary injury. Nitric oxide (NO) also contributes to tissue oxygen radical load, and although believed to be beneficial, its metabolites may play a pathophysiological role by participating in lipid peroxidation and isoprostane formation. We hypothesized that 8-iso-PGF2 alpha and NO levels increase in high oxygen concentrations and that 8-iso-PGF2 alpha is associated with lung injury and accumulation of plasma albumin in pulmonary extravascular space. Levels of 8-iso-PGF2 alpha in bronchial alveolar lavage fluid (BALF) of rats exposed to 90% O2 at 1 atmosphere for 48 h (56 +/- 3 pg/ml) or 60 h (70 +/- 5 pg/ml) were significantly increased compared with levels in ambient air-exposed control rats (36 +/- 5 pg/ml). NO levels in BALF of rats exposed to 90% O2 at 1 atmosphere for 60 h were increased 50% compared with NO levels in BALF of rats exposed to ambient air or 48 h of 90% O2 (P < 0.05). Accumulation of radiolabeled plasma albumin in lung parenchyma of rats inhaling 8-iso-PGF2 alpha was also examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Cytotoxicity of cis-parinaric acid in cultured malignant gliomas.

The cytotoxic effects of cis-parinaric acid, a plant-derived 18-carbon polyunsaturated fatty acid, were assessed in vitro on normal and neoplastic glia. After being incubated for 24 hours in the presence of 12 mumol/L cis-parinaric acid, 36B10 glioma cultures demonstrated nearly 90% toxicity (unpaired Student's t test, P < 0.001). Similar results were obtained after the exposure of C6 rat glioma cultures, A172 human glioma cultures, and U-937 human monocytic leukemia cultures to cis-parinaric acid. In contrast, fetal rat astrocytes incubated with 12 mumol/L cis-parinaric acid demonstrated no significant toxicity (3% reduction, P = 0.12); fetal rat astrocytes showed only 20% toxicity after exposure to 40 mumol/L cis-parinaric acid (P = 0.001). The cytotoxic effects of cis-parinaric acid were antagonized with the addition of equimolar concentrations of alpha-tocopherol. Enzyme immunoassay of treated 36B10 glioma supernatant fluid for 8-isoprostane (a known oxidative metabolite) demonstrated a 10-fold increase of 8-isoprostane over 24 hours (123.0 +/- 10.3 versus 10.0 +/- 0.7 pg/ml for control, P < 0.001). These studies indicate that cis-parinaric acid may be significantly cytotoxic to malignant glioma cells in concentrations that spare normal astrocytes and that the mechanism of cytotoxicity is related to an oxidative process. The selective cytotoxic effect of cis-parinaric acid we describe represents the first step in the development of new chemotherapeutic agents for gliomas; these new agents act by preferentially enhancing lipid peroxidation in neoplastic cells.

Animals↗