Gamma-Linolenic and Pinolenic Acids Exert Anti-Inflammatory Effects in Cultured Human Endothelial Cells Through Their Elongation Products.

SCOPE: Omega-3 fatty acids (FAs) from oily fish reduce cardiovascular disease. This may be partly due to modulation of endothelial cell (EC) inflammation. Fish stocks are declining and there is a need for sustainable alternative FAs. Gamma-linolenic acid (GLA) and pinolenic acid (PLA) are plant-derived FAs, which can fulfil this role. METHODS AND RESULTS: EA.hy926 cells are exposed GLA and PLA prior to stimulation with tumor necrosis factor (TNF)-α. GLA and PLA are incorporated into ECs, resulting in increases in long-chain derivatives produced by elongase 5, dihomo-gamma-linolenic acid (DGLA), and eicosatrienoic acid (ETA). Both GLA and PLA (50 µm) decrease production of soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein 1 (MCP-1), and regulated on activation, normal T cell expressed and secreted (RANTES). However, decreases in these mediators are not seen after pre-treatment with GLA or PLA in elongase 5 silenced EA.hy926 cells. DGLA and ETA (10 µm) decrease EC production of sICAM-1, MCP-1, RANTES, and IL-6. All FAs reduce adhesion of THP-1 monocytes to EA.hy926 cells. Both PLA (50 µm) and ETA (10 µm) decrease NFκBp65 phosphorylation. CONCLUSION: These effects suggest potential for GLA, PLA and their long-chain derivatives, DGLA and ETA, as sustainable anti-inflammatory alternatives to fish-derived FAs.

The pharmacodynamic profile of "Blackadder" blackcurrant juice effects upon the monoamine axis in humans: A randomised controlled trial.

Emerging evidence from human intervention trials indicates health benefits of consuming blackcurrant fruit, including improvements to cognitive performance, modulation of blood flow, regulation of blood glucose and inhibition of enzymes underpinning normal cognitive function. Of particular relevance is our previous demonstration of monoamine oxidase (MAO)-A and B inhibition after the consumption of a New Zealand "Blackadder" blackcurrant juice in humans. The current study uses a double-blind, placebo-controlled, randomised cross- over design to assess the pharmacodynamics of the effects on platelet MAO-B inhibition and associated substrates, plasma prolactin levels and blood glucose levels after consumption of a single serve of "Blackadder" blackcurrant juice standardised to 500 mg polyphenols. Eight healthy male (20--35 years) participants completed the trial. Measurements were obtained at baseline 15, 30, 45, 60, 100, 120, 150, 180, 240 mins and 24 h post dose. A fast, absolute and reversible inhibition of blood platelet MAO-B (P < 0.001) and a significant but delayed reduction in plasma prolactin (P < 0.001) were observed following the consumption of "Blackadder" blackcurrant juice when compared to a placebo control. No interpretable changes in substrates of MAO or associated metabolites were seen. These data provide a clear time course of the reversible inhibition of MAO-B after the single consumption of a of New Zealand "Blackadder" blackcurrant juice standardised at 500 mg of polyphenols and, therefore, provide a therapeutic window on which to base future nutritional interventions.

Consumption of functional fermented milk containing borage oil, green tea and vitamin E enhances skin barrier function.

As emerging studies show that skin functioning can be improved with orally imbibed ingredients, we decided to investigate a mixture of borage oil, catechins, vitamin E and probiotics, all known for their reported effects on epidermal function, in a fermented dairy product, for the first time. Gamma-linolenic acid (GLA) and catechins bioavailability and their effects on skin functionality have not been previously investigated from a fermented dairy product. Firstly, we assessed the bioavailability of GLA and catechins mixed in a fermented dairy matrix by measuring their levels in chylomicrons and plasma samples respectively. For the GLA contained in the dairy matrix, the area under the curve and time for maximal absorption were significantly different to the same kinetic parameters compared with absorption from the free oil indicating improved oral bioavailability. However, the overall absorption of catechins over the 6-h period was identical for both product forms. These results were sufficiently promising to warrant a 24 week skin nutrition intervention study in female volunteers having dry and sensitive skin. The product improved stratum corneum barrier function compared with a control product as early as 6 weeks after the consumption which continued throughout the rest of the study. The reduction in transepidermal water loss relative to control was maintained throughout the trial despite seasonal changes. Moreover, as a result of the enhanced bioavailability, a much greater effect on skin barrier function occurred than reported previously for the individual ingredients. Nevertheless, body mass index significantly influenced various outcome measurements of this study.

A randomised cross-over trial in healthy adults indicating improved absorption of omega-3 fatty acids by pre-emulsification.

BACKGROUND: The health benefits of increased intakes of omega-3 fatty acids are well established but palatability often presents a problem. The process of emulsification is used in the food industry to provide a wider spectrum of use, often with the result of increased consumption. Moreover, as emulsification is an important step in the digestion and absorption of fats, the pre-emulsification process may enhance digestion and absorption. In this study the levels of plasma fatty acid and triacylglycerol (TAG) following the ingestion of either an oil mixture or an emulsified oil mixture have been compared. METHODS: In this randomised cross-over study, 13 volunteers received the oil mixture and 11 received the oil emulsion as part of an otherwise fat free meal. Blood samples were collected at 0, 1.5, 3, 4.5, 6, 7.5 and 9 hours after ingestion of oil, separated and stored at -20 degrees C. Plasma triacylglycerols were assessed spectrophotometrically and fatty acids were determined by gas chromatography. Following a washout period of twenty days the procedure was repeated with the assignments reversed. RESULTS: The postprandial plasma TAG and the C18:3 (n-6), C18:3(n-3), C20:5(n-3) and C22:6 (n-3) polyunsaturated fatty acid (PUFA) levels for the emulsified oil group were increased significantly (P = 0.0182; P = 0.0493; P = 0.0137; P < 0.0001; P = 0.0355 respectively) compared with the non-emulsified oil group. The C16:0 and C18:0 saturated fatty acids, the C18:1 (n-9) monounsaturated fatty acid and the C18:2 PUFA were not significantly different for the oil and emulsified oil groups. CONCLUSION: Pre-emulsification of an oil mixture prior to ingestion increases the absorption of longer chain more highly unsaturated fatty acids (especially eicosapentaenoic acid and docosahexaenoic acid) but does not affect absorption of shorter chain less saturated fatty acids, suggesting that pre-emulsification of fish oils may be a useful means of boosting absorption of these beneficial fatty acids.

Distribution and metabolism of dihomo-gamma-linolenic acid (DGLA, 20:3n-6) by oral supplementation in rats.

We compared the dietary effects of dihomo-gamma-linolenic acid (DGLA) contained in the DGLA oil produced by a fungus with gamma-linolenic acid (GLA) on the fatty acid composition. Wistar rats were fed with three kinds of oil for two weeks as follows: (i) control group: corn oil; (ii) GLA group: borage oil; (iii) DGLA group: DGLA oil/safflower oil = 55:45. The DGLA concentrations in the liver, serum, and brain of the DGLA group were higher than those of the GLA oil group. We also examined the dose effect of DGLA. The DGLA levels in the liver, serum, and brain significantly increased with increasing dosage of DGLA in the diet. DGLA administration significantly increased the ratio of PGE1/PGE2 in the rat plasma. The mechanism for GLA administration to improve atopic eczema is thought to involve an increase in the concentration of DGLA metabolized from GLA, so these results suggest that the dietary effect of DGLA would be more dominant than GLA.

Simultaneous permeation of tamoxifen and gamma linolenic acid across excised human skin. Further evidence of the permeation of solvated complexes.

Tamoxifen is the hormonal treatment of choice in women who have hormone-dependent breast cancer and its efficacy in those women considered to have a high risk of developing breast cancer, has also been established. Gamma linolenic acid (GLA) has been shown to decrease the invasion of breast cancer and recent studies have demonstrated that GLA can enhance the oestrogen receptor down-regulation induced by tamoxifen. However, tamoxifen is associated with serious side-effects due mainly to systemic delivery, and targeted delivery of both tamoxifen and GLA would be highly beneficial. This work was a preliminary study for the development of a transcutaneous system to simultaneously deliver both tamoxifen and GLA directly to the breast. Full thickness human skin was dosed with 500 microl saturated solution of tamoxifen in borage oil (25% GLA) and the simultaneous permeation of the two actives determined. There was rapid flux with minimal lag time, the cumulative permeation at 24 h was 764.3 +/- 94.2 microg cm(-2) for GLA and 5.44 +/- 0.67 microg cm(-2) for tamoxifen: the latter being comparable to the amount of tamoxifen associated with cancerous breast tissue from a 20 mg oral dose. The ratio of GLA/tamoxifen permeated at different timepoints was quite consistent, both in terms of mass (mean 138, S.D. 15.1) and mols (mean 184, S.D. 20.3). It was determined that 2.5 molecules of GLA were associated with each molecule of tamoxifen in the permeation process, equating to a solvation cage of three molecules of triacylglycerol. This study has demonstrated the feasibility of administering simultaneously tamoxifen and GLA using borage oil as vehicle, which warrants further investigation as a novel topical two-component system in relation to or prophylaxis of those perceived at high risk of developing breast cancer. The study also provides further evidence of the permeation of solvated complexes across skin, rather than discrete penetrant molecules.

Inhibition of leukotriene synthesis, pharmacokinetics, and tolerability of a novel dietary fatty acid formulation in healthy adult subjects.

BACKGROUND: Numerous studies have explored dietary-management strategies for decreasing leukotriene synthesis by inflammatory cells through supplementation with polyunsaturated fatty acids such as gamma-linolenic acid (GLA) and eicosapentaenoic acid (EPA). OBJECTIVES: This study sought to determine the optimal daily intake, ratios, and formulation of dietary GLA and EPA required to safely reduce leukotriene biosynthesis in healthy individuals, and to evaluate the pharmacokinetics and safety profile of such a formulation. METHODS: Two preliminary trials were conducted to determine the minimum effective levels of GLA and EPA intake needed to reduce leukotriene biosynthesis and prevent increases in plasma arachidonic acid (AA) concentrations. These preliminary trials were followed by a single-center, randomized, double-blind, placebo-controlled, parallel-group, escalating-intake inpatient trial of a dietary GLA/EPA emulsion (PLT 3514) in healthy adult subjects. Subjects consumed either 10, 20, or 100 g of the PLT 3514 emulsion (respectively containing 0.75 g GLA + 0.5 g EPA, 1.5 g GLA + 1 g EPA, and 7.5 g GLA + 5 g EPA), or a placebo emulsion containing olive oil daily for 14 days. Plasma fatty acids were measured by gas chromatography Stimulated whole blood leukotrienes were measured by high-performance liquid chromatography with ultraviolet detection. RESULTS: Thirty subjects were included in the preliminary trials; 47 subjects were enrolled in the escalating-intake trial, of whom 42 completed the study. In the preliminary trials, intake of GLA 1.5 g/d in gelatin capsules decreased the capacity to synthesize leukotrienes but increased plasma levels of AA (both, P < 0.05). Inclusion of 0.25 or 1 g of dietary EPA prevented the increase in plasma AA concentrations. Dietary GLA and EPA showed significantly enhanced bioavailability when consumed in 20 g PLT 3514 emulsion compared with consumption in gelatin capsules (P < 0.05), resulting in a reduction in the amount of intake required to block leukotriene biosynthesis. Pharmacokinetic analyses indicated that fasting plasma GLA and EPA levels plateaued within 7 days' daily consumption at all levels of intake, whereas the time to maximum plasma concentration (Tmax) was shorter for GLA than for EPA. The Tmax was similar on days 1 and 14 for both GLA and EPA. There were no clinically significant between-group differences in changes in vital signs, mean clinical laboratory values, or abbreviated hematology laboratory tests, or significant differences in the occurrence of treatment-emergent adverse events between the group consuming up to 20 g/d of the GLA/EPA emulsion and the group consuming placebo. CONCLUSION: Consumption of specific proportions and intake levels of dietary GLA and EPA in a novel emulsion formulation inhibited leukotriene biosynthesis and appeared to be well tolerated in this population of healthy adult subjects.

Diet and asthma: has the role of dietary lipids been overlooked in the management of asthma?

OBJECTIVE: This article discusses the role of diet in the management of asthma. Readers will gain an understanding of how evolution of the western diet has contributed to increased asthma prevalence and how dietary modification that includes management of dietary lipids may reduce symptoms of asthma. DATA SOURCES: Relevant studies published in English were reviewed. STUDY SELECTION: Medline search to identify peer-reviewed abstracts and journal articles. RESULTS: Asthma and obesity, which often occur together, have increased in prevalence in recent years. Studies suggest adaption of a western diet has not only contributed to obesity, but that increased intake of specific nutrients can cause changes in the frequency and severity of asthma. Increased asthma prevalence has also been proposed to arise from increased exposure to diesel particles or lack of exposure to infectious agents or endotoxins during childhood, generating a biased Th2 immune response, and increased cytokine and leukotriene production. Antagonists directed against these pro-inflammatory mediators include anticytokines and antileukotrienes. A reduction in the levels of inflammatory mediators associated with asthma has also been seen with dietary interventions, such as the administration of oils containing gamma-linolenic acid and eicosapentaenoic acid. CONCLUSIONS: Evidence suggests elevated body mass index and dietary patterns, especially intake of dietary lipids, contribute to symptoms of asthma. Dietary modification may help patients manage their asthma as well as contribute to their overall health.

Intestinal absorption and lymphatic transport of a high gamma-linolenic acid canola oil in lymph fistula Sprague-Dawley rats.

A new canola strain capable of producing >30% gamma-linolenic acid [GLA, 18:3(n-6)] in the seed oil has been developed in our laboratories. This study compares the intestinal absorption and lymphatic transport of this newly developed high GLA content canola oil (HGCO) with traditional GLA-rich borage oil (BO) using a lymph fistula rat model. To assess the extent that 1 mL of GLA in the supplemented oil was absorbed and transported, the fatty acid compositions of triglycerides in mesenteric lymph were compared over a 24-h collection period. The digestion, uptake and lymphatic transport of HGCO and the normal physiologic changes associated with fat absorption (e.g., lymph flow and an increase in lymphatic endogenous lipids outputs, triglycerides, cholesterol and phospholipids) were similar in the HGCO-and the BO-fed rats. The original differences in gamma-linolenic acid content in HGCO and BO were preserved in the fatty acid composition of the rats' lymph lipid. We conclude that the HGCO derived from the genetically modified canola plant is absorbed and transported into lymph similarly to BO.

NMR and isotope ratio mass spectrometry studies of in vivo uptake and metabolism of polyunsaturates by the developing rat brain.

This article describes the application of in vivo 13C-nuclear magnetic resonance (NMR) spectroscopy and gas chromatography (GC)-combustion-isotope ratio mass spectrometry to the study of brain uptake and metabolism of polyunsaturated fatty acids in the suckling rat model. NMR spectroscopy is uniquely suited to the non-invasive detection of nonradioactive metabolites in living animals. We applied this approach to the noninvasive detection of 13C-arachidonate in brain and liver of living suckling rats but found that technical limitations in our model, mainly poor signal-to-noise, largely prevent useful results at this time. However, in a tracer study using simultaneous doses of 13C-gamma-linolenate and 13C-arachidonate, 13C-NMR of tissue lipid extracts quantitatively demonstrated a 10-fold greater (liver) or 17-fold greater (brain) accumulation of pre-formed vs newly synthesized arachidonate. GC-combustion-isotope ratio mass spectrometry was used to trace the utilization of [U-13C]-alpha-linolenate into three products in the brain: docosahexaenoate, cholesterol, and palmitate. The rationale was that although alpha-linolenate is used in de novo lipogenesis, the quantitative importance of this pathway is unknown. Our results in the suckling rat show that 2-13% of carbon from [U-13C]-alpha-linolenate appearing in brain lipids is in docosahexaenoate while the rest is in brain lipids synthesized de novo. Overall, these results indicate that the suckling rat brain prefers pre-formed to newly synthesized arachidonate and that alpha-linolenate is readily utilized in brain lipid synthesis. These methods are suited to comparative studies of the metabolism of polyunsaturates and they support previous observations that the metabolism of some polyunsaturates such as alpha-linolenate extends well beyond the traditional desaturation-chain elongation pathway.

Tissue distribution and metabolism of gamma-linolenoyl-3-eicosapentaenoyl propane diol enterally or intravenously administered to mice bearing human pancreatic carcinomas.

Synthetic propane diol lipids have been proposed as novel compounds to deliver cytocidal polyunsaturated fatty acids (PUFA) such as gamma-linolenic (GLA) and eicosapentaenoic (EPA) acids. To assess the biodistribution and metabolism of these PUFA in immunodeficient mice bearing human pancreatic carcinomas (AsPC-1), gamma-linolenoyl-3-eicosapentaenoyl propane diol (GE diol) was provided in a fat-free diet (5% w:w) for 6 weeks or parentally administered as 14C-GE diol (1 or 3 consecutive doses of 1.66 g/kg/day) in an innovative non-ionic-digalactosyldiacylglycerol emulsion. In tumor, liver, brain, kidney, plasma and fat tissue of mice fed GE diol, PUFA were increased over 25-fold, except for arachidonic acid (AA) levels, which were reduced or remained constant when compared to mice fed control corn oil diet. GLA and EPA were mainly stored in fat tissue. The recovery of radioactivity from the i.v. infected 14C-GE diol was dose and time dependent. Ten days after the i.v. infusion, GLA was only detected in substantial concentrations in tumor and in fat tissue (21 and 202 micrograms/g, respectively). Overall, these studies showed that: GE diol emulsions provide 640-fold higher doses of both GLA and EPA without causing hemolysis or adverse effects in the host mouse when compared to free PUFA infusions; GE diol is metabolized after oral or i.v. administration; tumor concentrations of GLA and EPA from the enterally administered diol were 4 to 13-fold higher than the in vitro cytotoxic levels; EPA, competes with AA and probably inhibits the activity of delta 5 desaturase without affecting the elongation of GLA in the host and tumor tissue; the change in PUFA profile modifies the substrates for eicosanoid synthesis. In short, a potentially desirable cytotoxic PUFA pattern can be achieved in host tissues and, in particular, in a human pancreatic tumor by providing GLA and EPA in the form GE-diol. These findings guarantee further investigations in oncology with this neutral diol lipid.

Acyloxymethyl acidic drug derivatives: in vitro hydrolytic reactivity.

A series of acyloxymethyl drug derivatives of the NH-acidic drugs, phenytoin and theophylline and of the carboxylic acid drugs, thioctic acid and indomethacin, were prepared in order to determine the effect of varying the nature of the drug on the in vitro rate of hydrolysis catalyzed by porcine liver esterase and human plasma. The acyl portion was comprised of either valeric acid (val) or gamma-linolenic acid (GLA). With the exception of some GLA prodrugs, the derivatives displayed first-order kinetics in both enzyme systems. The NH-acidic drug derivatives were hydrolyzed faster than the carboxylic drug derivatives by porcine liver esterase and human plasma. It was found that the short chain valeric acid derivatives were hydrolyzed faster than the GLA derivatives. The rates of hydrolysis for the relatively smaller prodrugs of theophylline and thioctic acid were greater than the rates of hydrolysis for the bulkier phenytoin and indomethacin prodrugs indicating steric hindrance was important. The lipophilicity index, log K, of the valeric acid drug derivatives was plotted against the logarithm of the hydrolysis rate constant, k, and it was observed that log k decreased with an increase in log K. A comparison of these results with those of previous studies where the alkyl and acyl moieties were varied of acyloxyalkyl theophylline derivatives has provided a rationale, based on lipophilicity, for the structure of a prodrug to be designed based on an in vitro desired rate of hydrolysis.

Intravesical chemotherapy with gamma linolenic acid becomes a realistic prospect in serum-free applications: in vitro cytotoxicity and systemic absorption studies.

PURPOSE: To assess the cytotoxicity of Meglumine gamma linolenic acid (MeGLA) in serum-free application on 2 urothelial cancer cell lines, to examine whether the instant kill action of MeGLA is retained in a serum free environment, and to study the pharmacokinetics of intravesical instillation of gamma linolenic acid (GLA). MATERIALS AND METHODS: The 2 human urothelial cancer cell lines (MGH-U1 & RT112) were utilized in classical cytotoxicity assays in which drug exposure lasted 2 hours in serum or in serum-free application. The thiozolyl blue (MTT) assay was used to quantify the residual viable biomass 5 days later. Immediate cytotoxicity was also compared in serum and serum-free application. Four Wistar rats were used to study the intravesical absorption profile of tritiated GLA (3H-GLA). RESULTS: There was a 10-fold enhancement of the lytic efficacy of MeGLA in serum-free application and this enhancement was also observed in experiments assessing instant kill. There was a similar enhancement of efficacy seen in the multi-drug resistant (MDR) clone of cells. The absorption profile showed < 2% of instilled counts were absorbed and the commonest destination for the absorbed GLA was the liver. CONCLUSIONS: The cytotoxic action of MeGLA was enhanced in serum free application. This enhancement was maintained when cells expressed the MDR phenotype. There was limited absorption from the bladder. MeGLA is a feasible intravesical agent for use in superficial bladder cancer.

Pharmacokinetic data of gamma-linolenic acid in healthy volunteers after the administration of evening primrose oil (Epogam).

Defects in the metabolism of gamma-linolenic acid are thought to play a major role in the pathogenesis of atopic eczema, but little is known about the pharmacokinetic behavior of this fatty acid and its metabolic products. We investigated the serum level-time courses of 8 fatty acids after the administration of Epogam, a preparation of evening primrose oil which contains gamma-linolenic acid as an active ingredient. From 6 volunteers, serum concentration time curves of gamma-linolenic acid and 7 other fatty acids were profiled 24 h with and without the administration of Epogam. Six capsules of Epogam were administered to each subject in the morning at 7:00 and further 6 capsules in the evening at 19:00. On the days of investigation the volunteers had a diet of low fat meals. The serum concentrations of the fatty acids were determined as their methyl esters by means of gas chromatography mass spectrometry. Gamma-linolenic acid shows an absorption-elimination pattern after the administration of Epogam and its AUC24h and Cmax are significantly increased over the baseline values. After the evening administration, t(max) is shorter (2.7 +/- 1.2 h) than after the morning administration (4.4 +/- 1.9 h). The other fatty acids show no significant increase in their concentrations, especially dihomo-gamma-linolenic acid and arachidonic acid, which are metabolic products of gamma-linolenic acid. Conclusively, an effect of the administration of gamma-linolenic acid on the serum concentrations of dihomo-gamma-linolenic acid and arachidonic acid and, therefore, on the biosynthesis of prostaglandin PGE1 and PGE2 could not clearly be established in healthy volunteers. Further investigations will show if there is a significant effect in patients suffering from atopic eczema.

In vivo and in vitro biotransformation of the lithium salt of gamma-linolenic acid by three human carcinomas.

Lipid metabolism has been considered recently as a novel target for cancer therapy. In this field, lithium gamma-linolenate (LiGLA) is a promising experimental compound for use in the treatment of human tumours. In vivo and in vitro studies allowed us to assess the metabolism of radiolabelled LiGLA by tumour tissue and different organs of the host. In vitro studies demonstrated that human pancreatic (AsPC-1), prostatic (PC-3) and mammary carcinoma (ZR-75-1) cells were capable of elongating GLA from LiGLA to dihomo-gamma-linolenic acid (DGLA) and further desaturating it to arachidonic acid (AA). AsPC-1 cells showed the lowest delta5-desaturase activity on DGLA. In the in vivo studies, nude mice bearing the human carcinomas were given Li[1-(14)C]GLA (2.5 mg kg(-1)) by intravenous injection for 30 min. Mice were either sacrificed after infusion or left for up to 96 h recovery before sacrifice. In general, the organs showed a maximum uptake of radioactivity 30 min after the infusion started (t = 0). Thereafter, in major organs the percentage of injected radioactivity per g of tissue declined below 1% 96 h after infusion. In kidney, brain, testes/ovaries and all three tumour tissues, labelling remained constant throughout the experiment. The ratio of radioactivity in liver to tumour tissues ranged between 16- and 24-fold at t = 0 and between 3.1- and 3.7-fold at 96 h. All tissues showed a progressive increase in the proportion of radioactivity associated with AA with a concomitant decrease in radiolabelled GLA as the time after infusion increased. DGLA declined rapidly in liver and plasma, but at a much slower rate in brain and malignant tissue. Seventy-two hours after the infusion, GLA was only detected in plasma and tumour tissue. The sum of GLA + DGLA varied among tumour tissues, but it remained 2-4 times higher than in liver and plasma. In brain, DGLA is the major contributor to the sum of these fatty acids. Data showed that cytotoxic GLA and DGLA, the latter provided either by the host or by endogenous synthesis, remained in human tumours for at least 4 days.

Vitamin E blocks the cytotoxic effect of gamma-linolenic acid when administered as late as the time of onset of cell death--insight into the mechanism of fatty acid induced cytotoxicity.

Certain polyunsaturated fatty acids can selectively kill tumor cell lines while causing little to no harm to normal cell lines. However, the mechanism of this cytotoxicity is only partially understood. Antioxidants such as vitamin E have been shown to be capable of completely blocking the cytotoxic response when administered concomitantly with the fatty acid. We report here that when vitamin E was added as late as 6 days following fatty acid treatment, at a time point when the process of cell death was well underway, any further development of cell death was blocked. This implies that the mechanism of fatty acid induced cytotoxicity does not involve a gradual compromising of the cell over the 5-7 day time course of cell death. Instead, the event triggering cell death is an oxidative phenomenon occurring over a short time span of minutes or hours, not days, and is completely blocked by vitamin E.