Mechanisms of the selective cytotoxic actions of certain essential fatty acids.

Polyunsaturated fatty acids (PUFA) have a selective cytotoxic/cytostatic effect on a number of tumor cell lines in culture. Although this process may be enhanced by the addition of iron there is a minimum level of PUFA necessary for potentiation of cell death. Vitamin E blocks PUFA cytotoxicity when added up to 5 days after fatty acid administration.

Exogenous gamma-linolenic acid alters hormone stimulated cyclic AMP levels in U937 cells.

Polyunsaturated fatty acids are selectively cytotoxic in culture. Incorporation of these fatty acids leads to profound changes in membrane fatty acid composition which in turn may alter the activity of transmembrane receptor/effector systems. In U937 cells, hormone stimulated production of cyclic AMP can be reduced by 30% following incubation with gamma-linolenic acid (18:3n-6).

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.

Distribution of plasma phosphatidylcholine molecular species in rabbits fed fish oil is modulated by dietary n-6 fatty acids.

The present study examined the distribution of plasma phosphatidylcholine (PC) molecular species in rabbits fed a chow diet supplemented with fish oil (FO) in combination with either hydrogenated coconut oil or the n-6 fatty acid-rich evening primrose oil (EPO) for 4 weeks. Significant proportions of plasma PC molecular species contained long-chain n-3 fatty acids. Addition of EPO to the FO supplemented diet increased the incorporation of n-6 fatty acids into plasma PC molecules; it also raised the proportions of 16:0-18:2, n-6, 18:1-18:2, n-6, 18:2, n-6-18:2, n-6, and 16:0-20:4, n-6.

Metabolism of n-6 fatty acids by NIH-3T3 cells transfected with the ras oncogene.

N-6 fatty acid metabolism was compared in NIH-3T3 cells and DT cells, which differ only in the presence of the v-Ki-ras oncogene. Non-dividing cells were incubated with [1-14C]-labelled fatty acids (18:2n-6, 18:3n-6, 20:3n-6 and 20:4n-6) at different time intervals (2-24 h) and concentration (0-120 microM). In both cells lines, the uptake of different fatty acids from the medium was similar and reached a maximum at 6-8 h.

The membrane hypothesis of schizophrenia.

The phospholipid structure of neuronal membranes is essential for normal functioning of the nervous system. Evidence is accumulating that phospholipid metabolism in both brain and red blood cells may be disturbed in schizophrenia. In particular, in patients with negative symptoms, levels of arachidonic acid and docosahexanoic acid in red blood cell membrane phospholipids are severely abnormal.

Liver delta 5 and delta 6 desaturase activity differs among laboratory rat strains.

This study was designed to examine the variations among rat strains in hepatic fatty acid desaturase activities and to determine the correlations between the activities of these enzymes and the levels of each microsomal fatty acid. Wistar rats from two different sources as well as Long-Evans and Sprague-Dawley rats were selected to assess, under standard and identical experimental conditions, the liver delta 5 and delta 6 desaturase activities. Both desaturase activities were significantly reduced by 56% in Sprague-Dawley rats when compared to BB-Wistar control rats, whereas intermediate reduced values were detected in Wistar (CR) and Long-Evans strains.

Differences in the metabolism of 18:2n-6 and 18:3n-6 by the liver and kidney may explain the anti-hypertensive effect of 18:3n-6.

The present study examined the in vitro and in vivo metabolism of 18:2n-6 and 18:3n-6 by kidney and liver in the male adult spontaneously hypertensive (SHR) and normotensive (WKY) rats. In liver and kidney slices incubated for 1 h with either [1-14C]18:2n-6 or [1-14C]18:3n-6 (60 microM), substantial amounts of radioactivity were incorporated into triacylglycerol and phospholipid fractions. Approximately 15% of the radiolabeled 18:2n-6 was converted into 18:3n-6 in liver slices but no conversion was found in kidney slices.

Effects of dietary protein and cholesterol on phosphatidylcholine and phosphatidylethanolamine molecular species in mouse liver.

The present study examined the effects of two atherogenic factors, animal protein and cholesterol, on the distribution of fatty acids and the molecular species of major liver phospholipids in mice. Weanling mice were fed a semisynthetic diet supplemented with either casein or soy protein (20%, w/w) in the presence or absence of 0.5% cholesterol for 4 wk.

Effects of maternal dietary n-3 and n-6 fatty acids (pre- and post-delta 6 desaturation) on tissue glycerophospholipid fatty acid compositions in dams and suckling mice.

The present study examined the effects of supplementation of either 18:3n-3 or a mixture of its post-delta 6-desaturation metabolites, 20:5n-3/22:6n-3, in combination with either 18:2n-6 or its immediate delta 6-desaturation product, 18:3n-6, in the maternal diet (n-3 to n-6 ratio at 0.25) on brain, liver, heart, and kidney glycerophospholipid fatty acid composition in dams (B6D2F1 mice) and their 12-day-old suckling pups. As expected, n-3 and n-6 fatty acids competed for incorporation into tissue glycerophospholipids in both dams and their suckling pups.

Variations in temperature and oxygen content do not alter levels of thiobarbiturate reactive material in human breast tumour cells (ZR-75-1) incubated with gamma-linolenic acid.

The mechanism by which tumour cells may be killed in vitro by exogenous polyunsaturated fatty acids may involve lipid peroxidation. Gamma-linolenic acid caused a dose and time-dependent reduction in ZR-75-1 cell growth. However, altering either the incubator temperature (35, 37 and 39 degrees C) or the oxygen content (16, 21 and 26%) had little effect on either the growth of cells in the presence of gamma-linolenic acid or on thiobarbiturate reactive material levels over a 7 day period.

Concentration-dependent effect of iron on gamma-linolenic acid toxicity in ZR-75-1 human breast tumor cells in culture.

Polyunsaturated fatty acids are cytotoxic to ZR-75-1 human breast tumor cells in culture. This effect may be potentiated by the simultaneous addition of iron. When cytotoxicity was measured in the presence of different concentrations of both gamma-linolenic acid and ferrous chloride there was an increase in cell death above concentrations of 9 microM and 0.

Metabolism of radiolabelled 18:2n-6 and 18:3n-6 by NIH-3T3 cells and the DT subclone.

The incorporation and metabolism of delta-6-desaturase substrate and product, [1-14C]-linoleic (18:2n-6) and [1-14C]-gamma-linolenic acid (18:3n-6), was examined in NIH-3T3 cells and the DT subclone which differs only in the presence of the v-Ki-ras oncogene. Similar amounts of post delta-6 and delta-5 desaturase metabolites were found in both cell lines indicating that the activity of these important enzymes of fatty acid metabolism was not affected by the expression of the oncogene. However, measurable quantities of the direct elongation product of 18:2n-6, 20:2n-6, were only found in DT cells.

Abnormalities in dihomo-gamma-linolenic acid release in the pathogenesis of hypertension.

Spontaneously hypertensive rats (SHR) respond to angiotensin and norepinephrine with an exaggerated pressor response. We have investigated the possibility that increased vascular reactivity in SHR may be related to a reduced synthesis of prostaglandin E1 (PGE1) resulting from a defect in the release of its precursor, dihomo-gamma-linoleic acid (DGLA). Isolated perfused mesenteric vascular beds of SHR and age matched Wistar-Kyoto rats (WKY) were perfused with Kreb's bicarbonate buffer.

Effects of saturated fatty acids on n-6 fatty acid metabolism in cultured human monocyte-like cells (U937).

Effects of supplementation of saturated fatty acids (16:0 and 18:0) on metabolism of the cytotoxic n-6 fatty acids in cultured human monocyte-like cells (U937) have been examined. U937 cells were incubated in 5% delipidated fetal bovine serum containing 16:0 and 18:0. Supplementation of either 16:0 or 18:0 has no significant effect on the uptake of 18:2n-6 and 18:3n-6.

Fatty acid metabolism in health and disease: the role of delta-6-desaturase.

Linoleic acid is the main dietary essential fatty acid (EFA). To be fully utilized by the body, it must be metabolized to a range of other substances. The first step in this pathway is delta-6-desaturation to gamma-linolenic acid (GLA).

Relationship between mouse liver delta 9 desaturase activity and plasma lipids.

This study was undertaken to investigate the total plasma fatty acid composition and the relationship between plasma triacylglycerol (TG) levels and liver delta 9 desaturase activity in mice fed n-3 and/or n-6 fatty acid or hydrogenated coconut oil (HCO) (maximum 25 mg/g) supplemented diets. Generally, plasma TG levels and delta 9 desaturase activity were inversely correlated with the ratio of the sum of long chain n-6 fatty acids to 18:2n-6 and to the ratio of the sum of long chain n-3 fatty acids to 18:n-3, but they were positively correlated with the ratio of products and substrates (18:1/18:0) of the enzyme in plasma total lipids. The n-3 fatty acid (mainly 20:5n-3) enriched diet, when compared to the HCO diet at 21 d, caused a significant reduction in plasma TG levels but not in delta 9 desaturase activity.

Comparison of the metabolism of alpha-linolenic acid and its delta 6 desaturation product, stearidonic acid, in cultured NIH-3T3 cells.

The incorporation and metabolism of alpha-linolenic acid (18:3n-3) and its delta 6 desaturase product, stearidonic acid (18:4n-3), were compared by NIH-3T3 cells. In the presence of fetal calf serum, cells accumulated exogenously added 18:3n-3 and 18:4n-3 apparently at the expense of oleic acid (18:1n-9). Both 18:3n-3 and 18:4n-3 were elongated and desaturated to eicosatetraenoic acid (20:4n-3), eicosapentaenoic acid (20:5n-3) and docosapentaenoic acid (22:5n-3), but not to docosahexaenoic acid (22:6n-3), and were incorporated into phospholipids and triacylglycerols.

Mechanism of lipid peroxidation in cancer cells in response to gamma-linolenic acid (GLA) analyzed by GC-MS(I): Conjugated dienes with peroxyl (or hydroperoxyl) groups and cell-killing effects.

We have investigated the nature of lipid peroxidation occurring in association with cancer-killing produced by gamma-linolenic acid (GLA) and iron (Fe) in cultured human breast cancer cells (ZR-75-1: ZR). UV-spectrophotometry, high performance liquid chromatography (HPLC) and gas chromatography (GC) or gas chromatography-mass spectrometry (GC-MS) have been used to analyze lipid peroxides and their derivatives. Formation of conjugated dienes (CD), the conversion of triphenylphosphine (TPP) to its oxide (TPPO), and the simultaneous production of hydroxy polyunsaturated fatty acids (PUFA-OHs) from these corresponding PUFAs hydroperoxides (PUFA-OOHs) were analyzed in the total lipid extract of ZR cells and of normal human skin fibroblasts (CCD-41Sk:Sk).

The effects of gamma-linolenic acid on breast pain and diabetic neuropathy: possible non-eicosanoid mechanisms.

Gamma-linolenic acid (GLA) has recently been found to be beneficial in the management of breast pain and of diabetic neuropathy. GLA is a precursor of unsaturated fatty acids which are important in membrane structures, as second messengers in their own right and as precursors of eicosanoids. While the mechanisms of GLA action are likely to be complex, non-eicosanoid effects are probably of substantial importance.

Effect of n-3 and n-6 fatty acids on hepatic microsomal lipid metabolism: a time course study.

The present study examines the time dependent effects of n-6 and n-3 polyunsaturated fatty acids on liver microsomal lipid metabolism in FVB mice fed a diet supplemented with a mixture of free fatty acids (mainly 18:3n-6 and 20:5n-3) at 25 mg/g diet. Significant changes in the fatty acid composition of total liver and microsomal lipids were observed after 7 days on the diets. Thereafter, some animals remained on the same diet while others were fed a diet supplemented with hydrogenated coconut oil (HCO).

Effect of heat inactivation and freezing on fatty acid composition of plasma and red blood cells.

The effect of heat inactivation and freezing on fatty acid composition of plasma and red blood cells was investigated. Analysis was completed at baseline; after freezing; after incubation; after incubation and subsequent freezing; after incubation, freezing and a second incubation; and after freezing and subsequent incubation. There were changes in fatty acid levels observed in all groups with the phospholipid fractions showing the greatest changes.