Eicosanoids Abstracts

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Reference 1

Ziboh VA Fletcher MP

Dose-response effects of dietary gamma-linolenic acid-enriched oils on human polymorphonuclear-neutrophil biosynthesis of leukotriene B4.

In: Am J Clin Nutr (1992 Jan) 55(1):39-45

The dose-dependent effect of dietary supplemented gamma-linolenic acid (GLA, 18:3n-6)-enriched borage oil (Bor) and black-currant oil on the ability of calcium ionophore-activated human polymorphonuclear neutrophils (PMN) to generate leukotriene B4 (LTB4) was investigated in adult healthy human volunteers. Significant (P less than 0.05) elevation of dihomo-gamma-linolenic acid (DGLA, 20:3n-6), an elongation product of GLA, was revealed in PMN phospholipids after ingestion of either 0.48 or 1.5 g GLA-enriched oil/d. This elevation of DGLA in the PMN phospholipids paralleled the decreased capacity of calcium ionophore-activated PMN to generate LTB4. Although the inhibition of LTB4 was greater with the ingestion of 1.5 g GLA- enriched BOR/d, it was not significantly different from the ingestion of 0.48 g/d. Taken together, dietary ingestion of GLA-fortified oils does modulate PMN generation of proinflammatory LTB4.


Reference 2

Palombo JD DeMichele SJ Lydon EE Gregory TJ Banks PL Forse RA Bistrian BR

Rapid modulation of lung and liver macrophage phospholipid fatty acids in endotoxemic rats by continuous enteral feeding with n-3 and gamma-linolenic fatty acids.

In: Am J Clin Nutr (1996 Feb) 63(2):208-19

Dienoic eicosanoids derived from phospholipid arachidonic acid (AA) in lung and liver macrophages promote leukosequestration, thrombosis, and tissue injury. Current enteral diets (diet A) are enriched with linoleic acid (LA), a precursor of AA. Novel diets low in LA and containing eicosapentaenoic acid (EPA) and gamma-linolenic acid (GLA) foster formation of less inflammatory eicosanoids. The study objective was to assess the rapidity and extent of LA and AA displacement in vivo from alveolar macrophage (AM phi), lung, and liver Kupffer and endothelial (KE) cell phospholipids in rats fed enterally with diets enriched with 5.3% (by wt) EPA and either 1.2% or 4.6% GLA (diets B and C, respectively). After surgical placement of catheters, the rats were fed enterally and co-infused intravenously with either endotoxin or vehicle continuously for 3 or 6 d. Rats given either diet B or C had significantly lower (P < 0.01) relative percentages of AA and LA within the AM phi, lung, and KE cell phospholipids, and concomitantly higher percentages of EPA compared with rats infused with diet A after 3 d of enteral feeding irrespective of endotoxin co-infusion. Incorporation of dihomo-gamma- linolenic acid (DHGLA), the metabolite of GLA, into lung and KE phospholipids was significant in rats given diet C. Most of the changes in fatty acid composition occurred by day 3. The polyunsaturated fatty acid composition of AM phi, lung, and KE cell phospholipids can be rapidly modified by continuous short-term enteral feeding with EPA- and GLA-enriched diets irrespective of concurrent endotoxemia.


Reference 3

Belch JJ Ansell D Madhok R O’Dowd A Sturrock RD

Effects of altering dietary essential fatty acids on requirements for non-steroidal anti-inflammatory drugs in patients with rheumatoid arthritis: a double blind placebo controlled study.

In: Ann Rheum Dis (1988 Feb) 47(2):96-104

In rheumatoid arthritis (RA) benefit from non-steroidal anti- inflammatory drugs (NSAIDs) is mediated through inhibition of the cyclo-oxygenase enzyme, thereby decreasing production of the 2 series prostaglandins (PGs). The lipoxygenase enzyme is intact, however, allowing leucotriene (LT) production, e.g., LTB4 (an inflammatory mediator). Treatment with evening primrose oil (EPO) which contains gamma-linolenic acid (GLA) leads to production of the 1 series PGs, e.g., PGE1, which has less inflammatory effects. Also LT production is inhibited. Eicosapentaenoic acid (EPA, fish oil) treatment provides a substrate for PGs and LTs, which are also less inflammatory. In this study 16 patients with RA were given 540 mg GLA/day (EPO), 15 patients 240 mg EPA and 450 mg GLA/day (EPO/fish oil), and 18 patients an inert oil (placebo). The aim of this study was to determine if EPO or EPO/fish oil could replace NSAID treatment in RA. The initial 12 month treatment period was followed by three months of placebo for all groups. Results at 12 months showed a significant subjective improvement for EPO and EPO/fish oil compared with placebo. In addition, by 12 months the patients receiving EPO and EPO/fish oil had significantly reduced their NSAIDs. After 3 months of placebo those receiving active treatment had relapsed. Despite the decrease in NSAIDs, measures of disease activity did not worsen. It is suggested that EPO and EPO/fish oil produce a subjective improvement and allow some patients to reduce or stop treatment with NSAIDs. There is, however, no evidence that they act as disease modifying agents.


Reference 4

Tate GA Mandell BF Karmali RA Laposata M Baker DG Schumacher HR Jr Zurier RB

Suppression of monosodium urate crystal-induced acute inflammation by diets enriched with gamma-linolenic acid and eicosapentaenoic acid [published erratum appears in Arthritis Rheum 1990 Jul;33(7):1046]

In: Arthritis Rheum (1988 Dec) 31(12):1543-51

A subcutaneous air pouch formed in Sprague-Dawley rats was used to study the effect of diets enriched in gamma-linolenic acid (GLA) (in plant seed oil) and eicosapentaenoic acid (EPA) (in fish oil) on acute inflammation induced by monosodium urate crystals. The GLA- enriched diet suppressed significantly the cellular phase of inflammation (polymorphonuclear leukocyte accumulation, crystal phagocytosis, and lysosomal enzyme activity), but it had little effect on the fluid phase (exudate volume and protein concentration). In contrast, the EPA-enriched diet suppressed the fluid phase but not the cellular phase of inflammation. The findings indicate that the fluid and cellular phases of acute inflammation can be controlled independently. A combined diet of fish oil and plant seed oil (EPA- enriched and GLA-enriched) reduced both the cellular and fluid phases of inflammation. Thus, dietary provision of alternative substrates for oxidative metabolism (other than arachidonic acid) modifies monosodium urate crystal-induced acute inflammation.


Reference 5

Karmali RA Donner A Gobel S Shimamura T

Effect of n-3 and n-6 fatty acids on 7,12 dimethylbenz (a) anthracene- induced mammary tumorigenesis.

In: Anticancer Res (1989 Jul-Aug) 9(4):1161-7

Numerous studies have consistently shown that vegetable oils containing linoleic acid enhance mammary tumorigenesis more effectively than fish oils containing eicosapentaenoic and docohexaenoic acids. The purpose of this investigation was to study these and additional n-3 and n-6 PUFA, e.g., a-linolenic (a-LN) (18:3 n-3) and gamma-linolenic (GLA) (18:3 n-6) acid. Different oils were used as dietary sources of fatty acids: corn (CO) (61% LA); blackcurrant (BCO) (44% LA, 18% GLA and 16% a-LN); fish oil (FO) (mixed with corn oil, 12% LA and 24% EPA + DPA + DHA). Thirty-five- day-old female Sprague-Dawley rats were divided into 5 dietary treatment groups and were allowed to feed ab libitum on one of the test diets: I. BCO (23.5%); II. CO (23.5%); III. BCO (15.5%) + FO (8%); IV. FO (20.5%) + CO (3%); and V. BCO (20.5%) + FO (3%). From 48 to 52 days of age, rats in all five groups were fed rat chow. At 50 days of age, all rats were given 5 mg DMBA by oral intubation, and 2 days later the test diets were resumed until termination of the experiment. Analysis of tumor incidence, and multiplicity data for 5 diet groups indicated that rats fed 23.5% CO (II) exhibited enhanced mammary tumor yields when compared to animals on the remaining 4 diets in the order II greater than I, III, V greater than IV. Since the level of fat (23.5% w/w) was similar in all 5 diets, and body weight gain was in the order IV greater than II greater than I, the results of this study indicate that differences in tumor yields were related to fatty acid composition of diets. In support of this conclusion, fatty acid profiles of RBC and tumor phosphoglycerides reflected dietary fatty acid composition. In groups I and II, even though tumor levels of LA were similar, the levels of GLA, DHLA (20:3 n-6) and a-LN were higher in I compared to II, suggesting that these differences may be associated with lower yields of DMBA-induced mammary tumors in group I. Incorporation of marine type n-3 PUFA (EPA, DPA and DHA) in tumor PL was greater in Group IV compared to plant type n-3 PUFA (a-LN) in Groups I, III, and V. Since tumor yields were the lowest in Group IV, these results suggest that incorporation of marine type n-3 PUFA into cell membranes does not favor development of DMBA-induced mammary tumors.


Reference 6

Begin ME Sircar S Weber JM

Differential sensitivity of tumorigenic and genetically related non- tumorigenic cells to cytotoxic polyunsaturated fatty acids.

In: Anticancer Res (1989 Jul-Aug) 9(4):1049-52

A series of closely related rat brain cell lines that differ in their ability to form tumors has been used to investigate the selectivity of cytotoxic polyunsaturated fatty acids. The colony-formation ability of tumorigenic F4 cells was markedly reduced when the cells were challenged with GLA and EPA. In contrast, the non-tumorigenic revertants were less affected. All retransformed tumorigenic variants exposed to GLA were as sensitive as their parental tumorigenic cells and more sensitive than the non-tumorigenic clones. However, two out of three retransformed tumorigenic variants exposed to EPA were less sensitive than either the parental tumorigenic or non-tumorigenic clones. The addition of ferrous chloride to the culture medium increased the cytotoxicity of GLA in tumorigenic but not in non- tumorigenic variants. These results suggest that tumorigenicity per se is characterized by a high sensitivity to PUFAs exogenously administered at appropriate concentrations and that the sensitivity is fatty acid specific.


Reference 7

Miller CC Ziboh VA

Gammalinolenic acid-enriched diet alters cutaneous eicosanoids.

In: Biochem Biophys Res Commun (1988 Aug 15) 154(3):967-74

There are reports that vegetable oils containing gammalinolenic acid (GLA) may exert beneficial effects on inflammatory skin disorders. To determine whether or not dietary GLA exerts any modulatory role on cutaneous eicosanoids, guinea pigs were fed either a control diet containing safflower oil (less than 0.5% GLA) or borage oil, a GLA- rich diet containing 25% GLA. After an 8-week feeding period, epidermal samples from both animal groups were analyzed for fatty acid composition and tissue eicosanoids. Analysis of epidermal neutral lipids and phospholipids in borage oil-fed animals showed a marked increase in GLA and its elongase product, dihomogammalinolenic acid (DGLA). Similarly, analysis of epidermal eicosanoids in the borage oil-fed animals revealed significant increases in the amounts of the 15-hydroxy fatty acid (15-OH-20:3n-6) and prostaglandin PGE1, both metabolites of DGLA. Since these metabolites have anti- inflammatory potential, our results suggest that increased dietary GLA could result in the generation of local anti-inflammatory metabolites thus providing a non-toxic approach to suppression of cutaneous inflammatory skin disorders.


Reference 8

Hrelia S Lopez Jimenez JA Bordoni A Nvarro SZ Horrobin DF Rossi CA Biagi PL

Essential fatty acid metabolism in cultured rat cardiomyocytes in response to either N-6 or N-3 fatty acid supplementation.

In: Biochem Biophys Res Commun (1995 Nov 2) 216(1):11-9

In this study we demonstrate that cultured rat cardiomyocytes possess the capacity to desaturate/elongate essential fatty acids (EFAs). Alpha-linolenic acid (ALA) conversion to higher metabolites was greater than linoleic acid (LA) conversion, according to the higher affinity of the delta-6-desaturase enzyme for the n-3 than for the n- 6 EFAs. Gamma-linolenic acid (GLA) supplementation to the culture medium had no influence on LA conversion; but the addition of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids significantly decreased the formation of interconversion products from LA. The conversion of ALA to higher metabolites was greatly affected by GLA; EPA had no effect on ALA conversion, while DHA significantly inhibited it. Both GLA (converted mostly to dihomo-gamma-linolenic acid) and EPA can be removed from phospholipids and addressed to prostanoid biosynthesis, so avoiding their potential accumulation and the inhibition of their own production. Our data clearly indicate that supplementation of the culture medium with either n-6 or n-3 fatty acids can cause reduced levels of the other series of fatty acids. This effect may be undesirable, since both n-6 and n-3 fatty acids are important in the prevention of coronary diseases.


Reference 9

Das UN Begin ME Ells G Huang YS Horrobin DF

Polyunsaturated fatty acids augment free radical generation in tumor cells in vitro.

In: Biochem Biophys Res Commun (1987 May 29) 145(1):15-24

Polyunsaturated fatty acids (PUFAs) have been shown to inhibit both normal and tumor cell growth in vitro. As PUFAs are known to induce a respiratory burst and free radical generation in polymorphonuclear leukocytes and since free radicals are toxic to cells, we investigated the effect of PUFAs on a measure of free radical generation (nitroblue tetrazolium reduction) in normal human fibroblasts and breast cancer cells in vitro. Results suggested that linoleate (LA), gamma-linolenate (GLA), arachidonate (AA) and eicosapentaenoate (EPA) can enhance nitroblue tetrazolium reduction in tumor cells but not in normal cells. GLA, AA and EPA were 1 1/2 to 2 times more effective than LA in inducing free radical generation. This difference was not due to increased uptake of LA, AA and EPA by tumor cells. In fact, the uptake of LA was the same both in normal and tumor cells whereas that of AA and EPA occurred at approximately half the rate in the tumor cells compared to normal cells. This indicates that PUFA induced growth inhibition and cytotoxicity to tumor cells may, at least in part, be due to enhanced free radical generation.


Reference 10

Madhavi N Das UN

Effect of n-6 and n-3 fatty acids on the survival of vincristine sensitive and resistant human cervical carcinoma cells in vitro.

In: Cancer Lett (1994 Aug 29) 84(1):31-41

Cis-unsaturated fatty acids of both the n-6 and n-3 series have been shown to be cytotoxic to a variety of tumor cells in vitro. Both gamma-linolenic acid (GLA) and eicosapentaenoic acid (EPA) can also augment the cytotoxicity of anticancer drugs. But, the effect of various cis-unsaturated fatty acids on the survival of tumor cells which are resistant to anticancer drugs has not been studied so far. Docosahexaenoic acid (DHA) and EPA of the n-3 series and GLA and dihomo-GLA (DGLA) of the n-6 series were found to be cytotoxic to both vincristine-sensitive (KB-3-1) and resistant (KB-ChR-8-5) human cervical carcinoma (HeLa-variant) cells in vitro. KB-ChR-8-5 was found to be only marginally less sensitive to the cytotoxic actions of all the fatty acids tested except arachidonic acid (AA) compared to KB-3-1. Cyclo-oxygenase inhibitor, indomethacin; lipoxygenase inhibitor, nordihydroguiaretic (NDGA); and calmodulin antagonists, trifluoperazine (TFP) and chlorpromazine (CPZ) were found to be ineffective in blocking the cytotoxic action of GLA, EPA and DHA, the most effective fatty acids, on KB-3-1 cells. This suggests that prostaglandins, leukotrienes and calmodulin do not have any role in the cytotoxic action of GLA, EPA, and DHA. On the other hand, the anti-oxidant, vitamin E, and the superoxide anion quencher, superoxide dismutase (SOD), could completely inhibit the cytotoxic action of GLA, EPA and DHA indicating a role for free radicals and, in particular, the superoxide anion in this process. This was supported further by the observation that GLA, EPA, and DHA can enhance the formation of superoxide anion, hydrogen peroxide, and lipid peroxides in KB-3-1 cells. GLA, EPA, and DHA-induced free radical generation and lipid peroxidation were also inhibited by vitamin E and SOD. These results suggest that GLA, EPA, and DHA are cytotoxic to both vincristine-sensitive and resistant human cervical carcinoma cells and that it is a free radical dependent process.


Reference 11

Fletcher MP Ziboh VA

Effects of dietary supplementation with eicosapentaenoic acid or gamma-linolenic acid on neutrophil phospholipid fatty acid composition and activation responses.

In: Inflammation (1990 Oct) 14(5):585-97

Previous data that alimentation with fish oil rich in eicosapentaenoic acid (EPA; 20:n-3) or vegetable oil rich in gamma- linolenic acid (GLA; 18:3n-6) can reduce symptoms of inflammatory skin disorders lead us to determine the effects of dietary supplements of oils rich in EPA or GLA on guinea pig (GP) neutrophil (PMN) membrane potential (delta gamma), secretion, and superoxide (O2- ) responses. Weanling GPs were initially fed diets supplemented with olive oil (less than 0.1% EPA; less than 0.1% GLA) for 2 weeks, followed by a crossover by two sets of animals to diets supplemented with fish oil (19% EPA) or borage oil (25% GLA). At 4-week intervals, 12% sterile casein-elicited peritoneal neutrophils (PMN) were assessed for membrane polyunsaturated fatty acid (PUFA) profiles and FMLP-, LTB4-, and PMA-stimulated delta gamma changes, changes in flow cytometrically measured forward scatter (FWD-SC) (shape change), 90 degrees scatter (90 degrees -SC) in cytochalasin B-pretreated-PMN (secretion response), and superoxide responses, GP incorporated EPA and GLA (as the elongation product, dihomo-GLA or DGLA) into their PMN phospholipids by 4 weeks. The peritoneal PMN of all groups demonstrated broad resting FWD-SC and poor activation-related FWD-SC increases, suggesting in vivo activation. While secretion was comparable in the three groups in response to FMLP, there was a trend toward inhibition of LTB4-stimulated 90 degrees -SC loss in both fish and borage oil groups. This was significant only with borage oil (21.7 +/- 2.1 vs 15.3 +/- 1.2% loss of baseline 90 degrees -SC, olive vs borage: P = 0.03). PMN from borage- and fish oil-fed GPs showed a progressively lower O2- response to FMLP than the olive oil group (73.9 +/- 3.9 and 42.9 +/- 6.8% of olive oil response for borage and fish oils, respectively; P less than 0.005 and P less than 0.01, respectively, at 12 weeks), while PMA-stimulated O2- was inhibited only in the fish oil-fed group and only at 12 weeks (62.0 +/- 2.7% of control; P less than 0.025). We conclude that dietary supplementation with oils rich in PUFAs can modify PMN activation responses.


Reference 12

Raederstorff D Pantze M Bachmann H Moser U

Anti-inflammatory properties of docosahexaenoic and eicosapentaenoic acids in phorbol-ester-induced mouse ear inflammation.

In: Int Arch Allergy Immunol (1996 Nov) 111(3):284-90

Laboratory animal models and clinical studies suggest that dietary n- 3 fatty acids are beneficial in diseases with an inflammatory component such as rheumatoid arthritis or psoriasis. In the present study we investigated the effect of purified docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on phorbol ester (TPA)-induced acute inflammation. Mice were fed for 6 weeks a diet containing 5% corn oil enriched with either 1% DHA or 1% EPA and compared with a group receiving 6% corn oil only. The dietary treatment with DHA or EPA elevated the n-3 polyunsaturated fatty acids as expected in the spleen and ear phospholipids, associated with a reduction in arachidonic acid levels. The degree of ear inflammation was quantified by measuring the four parameters including (1) edema as the increase in ear biopsy weight, (2) polymorphonuclear cell infiltration as myeloperoxidase activity (MPO) at the site of inflammation, (3) prostaglandin E2 (PGE2) and (4) leukotriene B4 (LTB4) concentrations in ear edema. The addition of DHA to the diet reduced significantly the edema formation and the MPO activity 24 h after TPA challenge. Both DHA and EPA significantly reduced the PGE2 and LTB4 levels compared with animals fed corn oil. This result suggests that DHA rather than EPA may be useful in the adjuvant treatment of diseases where acute inflammatory processes play a role.


Reference 13

Julu PO

Essential fatty acids prevent slowed nerve conduction in streptozotocin diabetic rats.

In: J Diabet Complications (1988 Oct-Dec) 2(4):185-8

Rats were given streptozotocin to induce insulin-dependent diabetes or citrate buffer alone in two experiments. Initially, the effect of 5 wks of dietary gamma-linolenic acid (GLA) plus eicosapentaenoic acid (EPA) on cutaneous nerve conduction velocity (CV) was examined. CV was determined by direct stimulation and recording from saphenous nerve under urethane anesthesia. Secondly, a 5 weeks study of supplementing the diet with GLA, GLA and EPA, or hydrogenated coconut oil (HC) was done. In addition, motor nerve CV was determined by directly stimulating sciatic nerve and recording from gastrocnemius muscle. The acute diabetes led to weight loss, and elevated blood glucose and glycosylated hemoglobin levels. Essential fatty acid (EFA) supplementation had no effect on any of these measures of severity of diabetes. In diabetic rats without EFA supplementation, CV of the myelinated fibers fell by 19-21%, while those receiving both GLA and EPA had normal CV. In diabetic rats receiving GLA alone, CV fell by 5-7%, which was significantly less than those without EFA supplementation (p less than 0.01 for cutaneous, and p less than 0.001 for motor nerves).


Reference 14

Palombo JD DeMichele SJ Lydon E Bistrian BR

Cyclic vs continuous enteral feeding with omega-3 and gamma-linolenic fatty acids: effects on modulation of phospholipid fatty acids in rat lung and liver immune cells.

In: JPEN J Parenter Enteral Nutr (1997 May-Jun) 21(3):123-32

Arachidonic acid (AA) present in lung and liver immune cell phospholipids is the precursor of eicosanoids that promote neutrophil margination, leading to tissue injury and inflammation. Administration of novel enteral formulations low in linoleic acid (LA) and containing eicosapentaenoic acid (EPA) from fish oil and gamma-linolenic acid (GLA) from borage oil displaces AA and promotes cell formation of eicosanoids with reduced inflammatory potential. The present study was undertaken to determine whether or not short- term provision of enteral diets containing GLA, EPA, or both in a cyclic fashion modulated the fatty acid composition of rat alveolar macrophage (AM) and liver Kupffer and endothelial (K&E) cell phospholipids in vivo to the extent achieved during continuous feeding. METHODS: Rats were isocalorically fed through a gastrostomy catheter for 3 or 6 days with high-fat, low-carbohydrate diets that were enriched with either LA (diet A), EPA (diet B), or EPA + GLA (diet C). The rats were randomized by infusion modality, ie, continuous vs cyclic (14 hours feeding with 10 hours fasting daily) feeding. AM and K&E were isolated and phospholipid fatty acid profiles were determined by gas chromatography. RESULTS: The dietary effects on AM and K&E cell phospholipid fatty acids for a given feeding period were not significantly influenced by the infusion modality. AM and K&E cells from rats receiving either diet B or diet C for 3 days had significantly lower AA and LA and higher EPA and dihomo-GLA (DHGLA), respectively, than rats given diet A regardless of the infusion modality. The mole % of EPA and DHGLA in K&E cells were higher after 6 vs 3 days of cyclic feeding with diet C. Using the eicosanoid precursor ratio (EPA + DHGLA/AA), the potential for generation of AA-derived eicosanoids was lower in rats given die B or C vs diet A regardless of infusion modality. DISCUSSION: Given the rapid changes in lung and liver immune cell phospholipid fatty acids, short-term provision of EPA and GLA-enriched diets cyclically or continuously may prove clinically relevant for modulating the fatty acid composition and potential eicosanoid formation by these cells.


Reference 15

Sellmayer A Danesch U Weber PC

Effects of different polyunsaturated fatty acids on growth-related early gene expression and cell growth.

In: Lipids (1996 Mar) 31 Suppl:S37-40

Effects of polyunsaturated fatty acids on expression of early- response genes c-fos and Egr-1 and induction of cell growth were assessed in Swiss 3T3 fibroblasts. Stimulation with arachidonic acid increased mRNA levels of c-fos and Egr-1. This effect was inhibited by preincubation with cyclooxygenase inhibitors and restored by addition of prostaglandin E2 (PGE2), the predominant eicosanoid produced in Swiss 3T3 fibroblasts. Further signaling of PGE2, was mediated by a protein kinase C-dependent pathway, since downregulation, or inhibition, of protein kinase C reduced increases in mRNA levels. Parallel to the stimulatory effects on mRNA levels, AA and PGE2 also increased cell growth, as determined by uptake of [3H]-thymidine. In contrast to arachidonic acid, n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) did not increase c-fos and Egr-1 mRNA levels or cell growth. Furthermore, preliminary data indicate that EPA and DHA even reduce the stimulatory effect of AA, which is associated with reduced formation of PGE2. In conclusion, our data indicate that AA increases expression of growth-related early genes c-fos and Egr-1 Swiss 3T3 fibroblasts by its conversion to PGE2 and subsequent activation of protein kinase C, whereas n-3 fatty acids do not activate this signaling cascade.


Reference 16

Ziboh VA

The significance of polyunsaturated fatty acids in cutaneous biology.

In: Lipids (1996 Mar) 31 Suppl:S249-53

The skin epidermis displays a highly active metabolism of polyunsaturated fatty acids (PUFA). Dietary deficiency of linoleic acid (LA) and 18-carbon (n-6) PUFA results in characteristic scaly skin disorder and excessive epidermal water loss. Arachidonic acid, a 20-carbon (n-6) PUFA is metabolized via the cyclooxygenase pathway into predominantly prostaglandin E2 (PGE2) PGF2 alpha, and PGD2 and via the lipoxygenase pathway into predominantly 15- hydroxyeicosatetraenoic acid (15-HETE). The prostaglandins modulate normal skin physiological processes at low concentrations and inflammatory reactions at high concentrations. Similarly, the very active epidermal 15-lipoxygenase transforms dihomogammalinolenic acid (DGLA) into 15-hydroxy eicosatrienoic acid (15-HETrE), eicosapentaenoic acid (EPA) into 15-hydroxyeicosapentaenoic acid (15- HEPE) and docosahexaenoic acid (DHA) into 17-hydroxydocosahexaenoic acid (17-HDoHE), respectively. These monohydroxy acids exhibit anti- inflammatory properties. In contrast, the 18-carbon (n-6) PUFA is transformed into 13-hydroxy-9,11-octadecadienoic acid (13-HODE), which exerts antiproliferative properties in the tissue. Thus, the supplementation of diets with appropriate purified vegetable oils and/or fish oil may generate local cutaneous anti-inflammatory metabolites which could serve as a less toxic in vivo monotherapy or as adjuncts to standard therapeutic regimens for the management of skin inflammatory disorders.


Reference 17

Nassar BA Huang YS Manku MS Das UN Morse N Horrobin DF

The influence of dietary manipulation with n-3 and n-6 fatty acids on liver and plasma phospholipid fatty acids in rats.

In: Lipids (1986 Oct) 21(10):652-6

The interrelations between linoleic acid (LA) metabolites and fish oil fatty acids were studied. Sprague-Dawley rats (200-220 g) were fed a fat-free semisynthetic diet supplemented with 10% (by weight) of different combinations of evening primrose oil (EPO), a rich source of LA and gamma-linolenic acid, and polepa (POL), a marine oil rich in eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. The combinations of supplement were as follows: 9% EPO-1% POL, 8% EPO-2% POL, 7% EPO-3% POL, 6% EPO-4% POL and 5% EPO-5% POL. After two weeks on the respective diets, the animals were killed, and the fatty acid compositions of liver and plasma phospholipids were examined. The results showed that animals fed higher proportions of POL consistently contained higher levels of dihomo-gamma-linolenic acid (DGLA) (p less than 0.05), a metabolite of LA and GLA, and lower levels of arachidonic acid (AA) (p less than 0.01), a metabolite of DGLA through delta-5-desaturation. Thus, an inverse relationship between AA/DGLA ratio and EPA levels was found to exist (r = -0.765 in plasma and -0.792 in liver). However, there was no such relationship between AA/DGLA ratio and DHA levels. This result suggested that EPA but not DHA in fish oil exerts an inhibitory effect on the conversion of DGLA to AA.


Reference 18

Raederstorff D Moser U

Borage or primrose oil added to standardized diets are equivalent sources for gamma-linolenic acid in rats.

In: Lipids (1992 Dec) 27(12):1018-23

The aim of this study was to evaluate the effect of different doses and sources of dietary gamma-linolenic acid (GLA) on the tissue phospholipid fatty acid composition. Rats fed four different levels of GLA (2.3, 4.6, 6.4 and 16.2 g of GLA/kg diet) in the form of either borage oil or evening primrose oil during 6 wk were compared with animals fed corn oil. The levels of dihomo-gamma-linolenic acid (DHLA) and GLA showed a significant dose-related increase in liver, erythrocyte and aorta phospholipids. Moreover, the arachidonic acid/DHLA ratios in tissues decreased with increasing intake of dietary GLA. There was no significant difference in tissue GLA and DHLA levels within groups given equal amounts of dietary GLA either as borage oil or evening primrose oil. The amount of dietary GLA administered did not significantly influence prostaglandin E2 production in stimulated aortic rings and thromboxane B2 levels in serum; however, an increase in prostaglandin E1 derived from DHLA was observed in the supernatants of stimulated aorta.


Reference 19

Booyens J Maguire L Katzeff IE

Dietary fats and cancer.

In: Med Hypotheses (1985 Aug) 17(4):351-62

The mono-unsaturated non-essential fatty acid oleic acid (OA) has been shown to stimulate malignant cell proliferation in culture significantly. In contrast, the essential fatty acids (EFAs) linoleic acid (LA) and alpha-linolenic acid (ALA) and their longer chain metabolic derivatives have been shown to have potent proliferation suppressive effects on malignant cells in culture. OA is normally synthesized in the body and present in most vegetable oils and therefore also in most experimental polyunsaturated fatty acid diets used for assessing the effects of dietary fatty acids on tumorigenesis in rats. Dietary OA could therefore specifically account for the general observation that diets containing polyunsaturated fatty acids (PUFAs) are tumorigenic (1). It has been repeatedly demonstrated that many EFAs and EFA metabolites suppress proliferation of a wide range of malignant cells in culture. These cytotoxic effects of EFAs do not inhibit the proliferation of nonmalignant cultured cells. The EFAs which have proliferation- suppression activities are components of cell membranes and many are also eicosanoid precursors. It is proposed that the membranes of malignant cells are inherently unstable. Thus the EFAs may have effects which either fluidise or stabilise these membranes. This results in either cytolysis or inhibition of proliferation. The relative quantities of the different EFAs may be critical for these effects. Eicosanoid metabolites may further compound these actions. It is suggested that one pathway for these actions could be a metabolic imbalance of EFA metabolites and their eicosanoid products. This would arise due to a combination of inhibited desaturase enzymes and a concomitant free cellular supply of dietary arachidonic acid (AA). This imbalance also could be causally involved in the promotion of malignancy. A simple procedure, which only involves dietary supplementation with gamma-linolenic acid (GLA) and eicosapentaenoic acid (EPA), is proposed as prophylaxis against the possible tumorigenic effect of dietary fats. “By some estimates, as much as 90% of all cancer in humans has been attributed to various environmental factors, including diet. The evidence reviewed by the committee suggests that cancers of most of the major sites are influenced by dietary patterns. The committee concluded that of all the dietary components it studied, the combined epidemiological and experimental evidence is most suggestive for a causal relationship between fat intake and the occurrence of cancer” – (1).


Reference 20

Bordoni A Lopez-Jimenez JA Spano C Biagi P Horrobin DF Hrelia S

Metabolism of linoleic and alpha-linolenic acids in cultured cardiomyocytes: effect of different N-6 and N-3 fatty acid supplementation.

In: Mol Cell Biochem (1996 Apr 12-26) 157(1-2):217-22

The metabolites of linoleic (LA) and alpha-linolenic (ALA) acids are involved in coronary heart disease. Both n-6 and n-3 essential fatty acids (EFAs) are likely to be important in prevention of atherosclerosis since the common risk factors are associated with their reduced 6-desaturation. We previously demonstrated the ability of heart tissue to desaturate LA. In this study we examined the ability of cultured cardiomyocytes to metabolize both LA and ALA in vivo, in the absence and in the presence of gamma linolenic acid (GLA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) alone or combined together. In control conditions, about 25% or LA and about 90% of ALA were converted in PUFAs. GLA supplementation had no influence on LA conversion to more unsaturated fatty acids, while the addition of n-3 fatty acids, alone or combined together, significantly decreased the formation of interconversion products from LA. Using the combination of n-6 and n-3 PUFAs, GLA seemed to counterbalance partially the inhibitory effect of EPA and DHA on LA desaturation/elongation. The conversion of ALA to more unsaturated metabolites was greatly affected by GLA supplementation. Each supplemented fatty acid was incorporated to a significant extent into cardiomyocyte lipids, as revealed by gas chromatographic analysis. The n-6/n-3 fatty acid ratio was greatly influenced by the different supplementations; the ratio in GLA+EPA+DHA supplemented cardiomyocytes was the most similar to that recorded in control cardiomyocytes. Since important risk factors for coronary disease may be associated with reduced 6-desaturation of the parent EFAs, administration of n-6 or n-3 EFA metabolites alone could cause undesirable effects. Since they appear to have different and synergistic roles, only combined treatment with both n-6 and n-3 metabolites is likely to achieve optimum results.


Reference 21

de Antueno RJ Cantrill RC Huang YS Raha SK Elliot M Horrobin DF

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

In: Mol Cell Biochem (1992 Dec 16) 118(2):153-61

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). With the exception of 20:5n-3 which showed a slower recovery, establishment of the HCO pattern was rapid indicating that the diet-induced changes could be easily reversed. The unsaturation index, the cholesterol/phospholipid ratio and the microviscosity of the microsomal membranes were not affected by these dietary manipulations. Unsaturated fatty acid supplementation reduced the activity of delta 9 desaturase by 50%. Feeding the HCO diet to mice previously fed the EPA/GLA diet led to a progressive increase in delta 9 desaturase activity, reaching 80% of the day zero values after 14 days. The monoene content of hepatic total lipids reflected, in most cases, the changes in enzyme activity. This study shows that a low dose of a n-3 and n-6 free fatty acid mixture increases the quantities of members of the n-3 family, without loss of n-6 fatty acids in microsomal membranes and modifies the activity of delta 9 desaturase without altering the microsome physicochemical parameters.


Reference 22

Tisdale MJ

Inhibition of lipolysis and muscle protein degradation by EPA in cancer cachexia.

In: Nutrition (1996 Jan) 12(1 Suppl):S31-3

Depletion of muscle and adipose tissue in cancer cachexia appears to arise not only from decreased food intake but also from the production of catabolic factors by certain tumours. Experiments with the cachexia-inducing MAC16 tumour in mice showed that when part of the carbohydrate calories were replaced by fish oil, host body weight loss was inhibited. The effect occurred without an alteration of either the total calorie consumption or nitrogen intake. Instead, one of the polyunsaturated fatty acids (PUFA) in fish oil, eicosapentaenoic acid (EPA), was found directly to inhibit tumour- induced lipolysis. The effect was structurally specific, as two related PUFA, docosahexaenoic acid (DHA) and gamma-linolenic acid (GLA), were without effect. The antilipolytic effect of EPA arose from an inhibition of the elevation of cyclic AMP in adipocytes in response to the lipid mobilizing factor. The increased protein degradation in the skeletal muscle of cachectic animals was also inhibited by EPA. This effect was due to the inhibition of the rise in muscle prostaglandin E2 in response to a tumour-produced proteolytic factor by EPA. Thus, reversal of cachexia by EPA in this mouse model results from its capacity to interfere with tumour- produced catabolic factors. Similar factors have been detected in human cancer cachexia.


Reference 23

Holler C Auinger M Ulberth F Irsigler K

Eicosanoid precursors: potential factors for atherogenesis in diabetic CAPD patients?

In: Perit Dial Int (1996) 16 Suppl 1:S250-3

Prostaglandins, thromboxanes, and other eicosanoids represent a widespread lipid-mediator system for intercellular signalling, and, hence, have multiple cellular actions. Thus it is not surprising that numerous events in the pathogenesis of atherosclerosis are associated with an altered formation of eicosanoids. To reconsider the availability of eiconsanoid precursors as one possible cause of atherogenesis, the dietary intake and the serum concentrations of arachidonic acid (AA) and eicosapentaenoic acid (EPA) were determined in patients with high risk for atherosclerosis on continuous ambulatory peritoneal dialysis (CAPD) with and without diabetes in comparison to healthy controls and diabetic patients without late complications. The factor AA/EPA in serum was created as a marker for the atherosclerosis risk. The setting was in a CAPD unit in one city hospital. There were 26 CAPD patients [9 with insulin-dependent diabetes mellitus (IDDM), 9 with noninsulin-dependent diabetes mellitus (NIDDM), and 8 without diabetes], 27 IDDM without late complications, and 41 healthy control persons. The AA levels in serum were significantly higher in all of the CAPD groups. In contrast, the EPA concentrations in serum were significantly lower in the CAPD groups, with the lowest EPA levels found in the CAPD-IDDM group. Therefore, the factors AA/EPA in serum were significantly higher in all of the CAPD groups, and again significantly higher in the CAPD- IDDM group than in the other CAPD groups. No differences in the amount of dietary intake of AA existed between the groups. The daily intake of EPA was significantly highest in the control group. Higher concentrations of AA and a lack of n-3 fatty acids lead in the presence of a reduced prostaglandin I2 biosynthesis, to a higher formation rate of potentially proatherogenic metabolites such as thromboxane A2, a vasoconstricting and platelet aggregating agent. Thus, the quotient AA/EPA could possibly be used as a marker of atherogenicity in the future.


Reference 24

Murray MJ Zhang T

The incorporation of dietary n-3 polyunsaturated fatty acids into porcine platelet phospholipids and their effects on platelet thromboxane A2 release.

In: Prostaglandins Leukot Essent Fatty Acids (1997 Mar) 56(3):223-8

We investigated the dynamic changes in fatty acid (FA) composition in platelet phospholipid (PL) and in the release of thromboxane from stimulated platelets in pigs prefed a diet enriched with polyunsaturated fatty acids (PUFA) of the n-3 and n-6 families of FAs. For 20 days, we fed pigs diets supplemented with either corn oil, fish oil, or fish and borage oil. Platelets were separated from blood drawn at baseline and then on day 4, 8, 12, 16 and 20 of the dietary regimen. Analysis of the FA contained in platelet PL demonstrated that significant changes in PUFA composition occurred during dietary supplementation with fish oil and fish and borage oil. Eicosapentaenoic acid (EPA) from fish oil was rapidly incorporated into PL of platelets and reached a steady-state plateau by day 12. An increase in the content of docosahexaenoic acid (DHA) in the platelets’ PL was observed in both groups receiving fish oil. This increase in n-3 PUFA in platelet PL occurred with a concomitant decrease in the content of n-6 FA, primarily of arachidonic acid (AA) in the PL of platelets in both fish oil groups. Dietary supplementation with borage oil, which contains gammalinolenic acid (GLA), increased dihomogammalinolenic acid (DGLA) content in platelet PL. Following A23187 stimulation of platelets, levels of thromboxane B2 (TxB2), the stable metabolite of thromboxane A2 (TxA2), were significantly suppressed in both fish oil groups compared to the corn oil-supplemented group. Dietary supplementation of EPA and EPA plus GLA increased platelet PL content of EPA, and EPA and DGLA, respectively. Following platelet stimulation, TxA2 production was significantly increased, an increase that was attenuated in the platelets from pigs prefed fish oil, and even more so in the fish and borage-oil-prefed pigs.


Reference 25

Navarette R Tang W Ziboh VA

Dietary intake of concentrated gamma-linolenic acid (GLA)-enriched oil suppresses cutaneous level of dihomo-gamma-linolenic acid (DGLA): possible in vivo inhibition of microsomal elongation of GLA to DGLA.

In: Prostaglandins Leukot Essent Fatty Acids (1992 Jun) 46(2):139-44

The dietary supplementation of normal guinea-pig diet with moderate levels of vegetable oils containing gamma-linolenic acid (GLA) is associated with elevation of epidermal levels of dihomo-gamma- linolenic acid (DGLA) and 15-hydroxyeicosatrienoic acid (15- lipoxygenase product of DGLA). However, supplementation of diet with higher level (70%) of GLA (GLA-70) resulted in marked decrease of epidermal level of DGLA. This nutritional observation prompted us to investigate in vitro the effects of varying concentrations of polyunsaturated fatty acids (PUFAs) on rat liver microsomal chain elongation of GLA into DGLA. Our data revealed that low concentrations of GLA (less than 100 microM) are stimulatory on the chain elongation while higher concentrations (greater than 100 microM) are inhibitory. The 18-carbon linoleic acid (precursor of GLA) was also markedly inhibitory at high concentrations. Interestingly, the longer chain 20-carbon n-3 PUFAs: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) exerted negligible effect. The results suggest that increased systemic presence of free PUFAs, such as may occur in vivo after dietary intake of high n-6 PUFA- containing vegetable oils, may explain the decreased level of DGLA in the epidermal tissue.


Reference 26

du Toit PJ van Aswegen CH du Plessis DJ

The effect of gamma-linolenic acid and eicosapentaenoic acid on urokinase activity.

In: Prostaglandins Leukot Essent Fatty Acids (1994 Aug) 51(2):121-4

Urokinase (UK) is an important protease enzyme in carcinogenesis, and is involved in the invasion and metastasis of cancer. Thus, regulation of UK activity is likely to be important in healthy cell metabolism. As it has been reported that a decrease in delta 6- desaturated essential fatty acid (EFA) metabolites occurs in malignant cells and that gamma-linolenic acid (GLA) and eicosapentaenoic acid (EPA) exert antimutagenic effects, the effects of GLA and EPA on UK activity have been investigated in this study. Both GLA (n-6) and EPA (n-3) acted as competitive inhibitors of UK with Ki values of 120 and 96 microM respectively. No modification of plasmin activity occurred with either 1.4 x 10(-4) M GLA or EPA. These results could explain why malignant cells with decreased EFA concentrations show increased UK activity. The addition of EFAs to available therapeutic regimens may be worth considering in the treatment of cancer.


Reference 27

Graham J Franks S Bonney RC

In vivo and in vitro effects of gamma-linolenic acid and eicosapentaenoic acid on prostaglandin production and arachidonic acid uptake by human endometrium.

In: Prostaglandins Leukot Essent Fatty Acids (1994 Jun) 50(6):321-9

This study examines the effect of a 6 month dietary supplement of either gamma-linolenic acid (GLA) or eicosapentaenoic acid (EPA) on the synthesis of prostaglandins E2 and F2 alpha by the endometrium of women with regular menstrual cycles. Samples of endometrium, obtained pre- and post-treatment, were incubated in vitro for 2 h and the prostaglandins E2 and F2 alpha released into the medium measured by radioimmunoassay. The ability of the tissue to take up 14C- arachidonic acid before and after treatment was also examined. Both GLA and EPA caused a marked decrease in the synthesis of prostaglandins E2 and F2 alpha (P < 0.001) but under the experimental conditions used, there was no consistent effect on arachidonic acid uptake. Body mass index, serum testosterone, fasting insulin and serum sex hormone-binding globulin (SHBG) concentrations did not change during the 6 month treatment period. An effect of GLA and EPA on arachidonic acid uptake into endometrial tissue explants was demonstrated in vitro. In the presence of both GLA and EPA, uptake into phospholipids (particularly phosphatidylcholine) decreased while uptake into triglycerides increased. Free 14C-arachidonic acid levels (that which could not be removed from the tissue by washing) also increased. Suppression of endometrial prostaglandin E2 and F2 alpha synthesis following GLA or EPA supplementation can be explained as direct competition between these fatty acids and arachidonic acid (the precursor of 2-series prostaglandins) for incorporation into membrane phospholipids. The amount of arachidonic acid available for 2-series prostaglandin synthesis will therefore be reduced. However, other mechanisms may exist which need to be investigated.(ABSTRACT TRUNCATED AT 250 WORDS)


Reference 28

Mengeaud V Nano JL Fournel S Rampal P

Effects of eicosapentaenoic acid, gamma-linolenic acid and prostaglandin E1 on three human colon carcinoma cell lines.

In: Prostaglandins Leukot Essent Fatty Acids (1992 Dec) 47(4):313-9

Several studies have demonstrated that certain essential fatty acids present a specific cytotoxicity for tumor cells. However, no investigation of this type has been performed on human colon cancer cells to date. This study investigated the effect of gamma-linolenic acid (GLA), eicosapentaenoic acid (EPA) and prostaglandin (PG) E1 on the proliferation and metabolism of three human colon cancer cell lines: HT 29, HRT 18, and CACO 2. GLA, EPA and PGE1 all inhibited the proliferation of the three cell lines, but with a decreasing gradient of sensitivity: HRT 18 > HT 29 > CACO 2, and with different IC50 values. PGE1 was markedly less effective than the other two. GLA and EPA increased lipid peroxidation and membrane fluidity in a dose- dependent manner. The presence of indomethacin did not modify the effects of GLA and EPA. In addition, PGE1 had little effect on membrane fluidity and lipid peroxidation. The antitumoral effect thus does not appear to be mediated by PGE1. Addition of vitamin E decreased the effects of GLA and EPA, which supports the hypothesis of direct action by these fatty acids. In conclusion, while EPA and GLA have an antitumoral effect in vitro, their effect on primary cultures of normal human colon cells must be investigated to determine whether this effect is specific to tumoral cells, as has been observed for other cell types.


Reference 29

Begin ME Das UN Ells G Horrobin DF

Selective killing of human cancer cells by polyunsaturated fatty acids.

In: Prostaglandins Leukot Med (1985 Aug) 19(2):177-86

Polyunsaturated fatty acids killed incubated human breast, lung and prostate cancer cells at concentrations which had no adverse effects on normal human fibroblasts or on normal animal cell lines. The most consistent and selective effects were obtained with fatty acids containing 3, 4 and 5 double bonds. When human cancer cells and normal human fibroblasts were co-cultured in the absence of polyunsaturated fatty acids, the malignant cells overgrew the normal ones. When eicosapentaenoic acid (EPA, 20:5n-3), gamma-linolenic acid (GLA, 18:3n-6) or arachidonic acid (AA, 20:4n-6) were added to the co- cultures, the normal cells outgrew the malignant ones. These observations suggest that treatment of malignancy with polyunsaturated fatty acids may have considerable potential while being associated with a high level of safety.


Reference 30

Burgess NA Reynolds TM Williams N Pathy A Smith S

Evaluation of four animal models of intrarenal calcium deposition and assessment of the influence of dietary supplementation with essential fatty acids on calcification.

In: Urol Res (1995) 23(4):239-42

Firstly, to determine a satisfactory animal model for induction of intrarenal calcification, a study of four previously described animal models of intrarenal calcification was carried out which showed that intraperitoneal injection of 10% calcium gluconate into female Sprague-Dawley rats was most effective. We then investigated the hypothesis that dietary supplementation with essential fatty acids could reduce the intrarenal calcification developing as a result of intraperitoneal calcium injection. Using a combination of fish oil and evening primrose oil, we demonstrated a significant difference in renal parenchymal calcification, which was 940 +/- 240 micrograms Ca/g dry weight renal parenchyma in unsupplemented animals and 320- 370 +/- 55-65 micrograms Ca/g dry weight renal parenchyma in supplemented animals (means +/- SEM, P < 0.005). It was also demonstrated that there was synergism between eicosapentaenoic acid (EPA) and gamma-linolenic acid (GLA): dietary supplementation with a combined oil preparation containing 27 mg/ml EPA and 67 mg/ml GLA mixed as 2% with food was as effective as oils containing either 400 mg/ml EPA or 80 mg/ml GLA mixed as 4% of food.


Reference 31

D’Almeida A Carter JP Anatol A Prost C

Effects of a combination of evening primrose oil (gamma linolenic acid) and fish oil (eicosapentaenoic + docahexaenoic acid) versus magnesium, and versus placebo in preventing pre-eclampsia.

In: Women Health (1992) 19(2-3):117-31

In a placebo controlled, partially double-blinded, clinical trial, a combination of evening primrose oil and fish oil was compared to Magnesium Oxide, and to a Placebo in preventing Pre-Eclampsia of Pregnancy. All were given as nutritional supplements for six months to a group of primiparous and multiparous pregnant women. Some of these women had personal or family histories of hypertension (21%). Only those patients who received prenatal care at the Central Maternity Hospital for Luanda were included in the study. Compared to the Placebo group (29%), the group receiving the mixture of evening primrose oil and fish oil containing Gamma-linolenic acid (GLA), Eicosapentaenoic acid (EPA), and Docosahexaenoic acid (DHA) had a significantly lower incidence of edema (13%, p = 0.004). The group receiving Magnesium Oxide had statistically significant fewer subjects who developed hypertension of pregnancy. There were 3 cases of eclampsia, all in the Placebo group.


Reference 32

Ziboh VA Chapkin RS

Biologic significance of polyunsaturated fatty acids in the skin.

In: Arch Dermatol (1987 Dec) 123(12):1686a-1690

Deficiency of essential fatty acid (EFA) containing linoleic acid (18:2n-6) in humans or animals induces morphologic changes characterized by severe scaly dermatosis, extensive percutaneous water loss, and hyperproliferation of the epidermis. Microscopically, the epidermis is characterized by hyperkeratosis and acanthosis. The refeeding of safflower oil containing linoleic acid or primrose oil (containing linoleic acid [18:2n-6] and gamma-linolenic acid [18:3n- 6]) acids to EFA-deficient guinea pigs reverses the EFA-deficiency symptoms. In contrast, replacement of safflower oil with menhaden fish oil, (containing eicosapentaenoic acid [20:5n-3] and docosahexaenoic acid [22:6n-3]) did not reverse the symptoms of EFA deficiency. These results indicate: (1) that an understanding of the roles of vegetable or fish oil in skin must evolve from an understanding of the roles of each constituent n-6 or n-3 fatty acid, and (2) that the n-3 fatty acids may function to modulate the metabolism and function of the n-6 fatty acids in vivo.


Reference 33

Akoh CC Chapkin RS Lewis RE


In: FASEB J (1990) 4(3):A796

Dietary fish oils (FO) are generally considered to have anti- inflammatory properties due in part to the competitive inhibition of macrophage arachidonic acid (20:4n-6) metabolism by n-3 fatty acids. To further determine how FO feeding may act to influence macrophage function, mice were fed complete diets containing either 9% by weight FO supplemented with 1% corn oil (CO) containing linoleic acid (18:2n- 6), 10% CO, or 10% borage oil (BO) containing 18:2n-6 and gammalinolenic acid (18:3n-6). After 2 wk, an acute inflammatory episode was induced by injecting unopsonized zymosan into the peritoneal cavity 1 hr prior to sacrifice. Peritoneal exudates were subsequently analyzed for in vivo leukotriene E4 (LTE4) production by combined solid-phase extraction and reverse-phase HPLC. In addition, phagocytosis of zymosan was determined by light and electron microscopy. Peritoneal exudates from CO and BO animals contained 5 times more LTE4 than FO exudates (BO, 37.5 and CO, 29.6 vs FO, 6.5 ng/mouse). The fraction of FO macrophages ingesting zymosan was 62.2% compared to 32.6% in BO- and 35.0% in CO-fed animals. The mean number of particles ingested per macrophage was also elevated in FO, 4.31 vs BO, 3.51 and CO, 3.57. These results indicate that dietary FO is capable of suppressing macrophage eicosanoid metabolism and enhancing zymosan phagocytosis in vivo.


Reference 34

Fan YY Chapkin RS Ramos KS

Dietary lipid source alters murine macrophage/vascular smooth muscle cell interactions in vitro.

In: J Nutr (1996 Sep) 126(9):2083-8

This study was conducted to compare the impact of dietary lipids on the ability of macrophages to modulate vascular smooth muscle cell (SMC) DNA synthesis in vitro. C57BL/6 female mice were fed six different diets (6 mice/diet) containing 10% fat from corn oil (CO), borage oil (BO), primrose oil (PO), fish-corn oil mix (FC, 9:1, w/w), fish-borage oil mix (FB, 1:3, w/w), or fish-primrose oil mix (FP, 1:3, w/w) for 2 wk. Peritoneal macrophages were isolated from these mice, stimulated with zymosan or vehicle, and subsequently co- cultured with naive mouse aortic SMC in the presence of 3H-thymidine to measure SMC DNA synthesis. In this co-culture system, macrophages were seeded on 25-mm culture inserts (upper chamber) and SMC were seeded on 35-mm culture dishes (lower chamber). The two cell types were separated by a semipermeable membrane with a 30-kD cut-off. When quiescent SMC were co-cultured with macrophages, only the PO and FP diet groups had significantly (P < 0.05) lower SMC DNA synthesis compared with the control CO group whose diet contained no gamma- linolenic acid (GLA) or (n-3) polyunsaturated fatty acids (PUFA). In contrast, when cycling SMC were co-cultured with diet-modulated macrophages, all dietary groups except for those fed FC had significantly lower (P < 0.05) SMC DNA synthesis relative to the CO group. Although the level of GLA in PO and BO diets was different (11.5 and 22.3 g/100 g fatty acids, respectively), these treatments exerted comparable inhibitory effects on SMC DNA synthesis. The FP treatment consistently exhibited the lowest SMC DNA synthetic profile among the six dietary groups irrespective of SMC growth conditions. These data suggest that BO and PO alone or in combination with fish oil influence macrophage/smooth muscle cell interactions in a manner consistent with favorable modulation of the atherogenic process.


Reference 35

Fan YY Chapkin RS

Mouse peritoneal macrophage prostaglandin E1 synthesis is altered by dietary gamma-linolenic acid.

In: J Nutr (1992 Aug) 122(8):1600-6

The ability of dietary gamma-linolenic acid [18:3(n-6)] to modulate prostaglandin biosynthesis in mouse resident peritoneal macrophages was determined. Mice were fed diets containing corn oil, borage oil or evening primrose oil or a mixture of borage and fish oils. After 2 wk, resident peritoneal macrophages were isolated and stimulated with unopsonized zymosan to induce prostaglandin synthesis. Borage oil, primrose oil and fish-borage oil mixture dietary groups (containing 25.6, 11.9 and 19.5 g gamma-linolenic acid/100 g fatty acids, respectively) had significantly (P less than 0.05) enhanced prostaglandin E1 synthesis (39.7, 29.4 and 73.0 nmol prostaglandin E1/mg protein, respectively) compared with corn oil-fed (containing less than 0.1 g gamma-linolenic acid/100 g fatty acids) animals, which synthesized less than 0.1 nmol prostaglandin E1/mg protein. Borage oil- and fish-borage oil mixture-fed mice had the highest biosynthetic ratio of prostaglandin E1/prostaglandin E2 (E1/E2 approximately 0.2). Macrophages from borage oil-fed mice synthesized the lowest amount of prostacyclin (198.7 nmol 6-keto-prostaglandin F1 alpha/mg protein) compared with corn oil-, primrose oil- and fish- borage oil mixture-fed mice (379.7, 764.8 and 384.2 nmol 6-keto- prostaglandin F1 alpha/mg protein, respectively). In addition, borage oil-, primrose oil- and fish-borage oil mixture-fed mice had significantly (P less than 0.05) higher levels of dihomo-gamma- linolenic acid [20:3(n-6)] in membrane phospholipids (5.5, 3.5 and 5.7 mol/100 mol, respectively) relative to corn oil-fed mice (2.0 mol/100 mol).


Reference 36

Chapkin RS Carmichael SL

Effects of dietary n-3 and n-6 polyunsaturated fatty acids on macrophage phospholipid classes and subclasses.

In: Lipids (1990 Dec) 25(12):827-34

This study examined the effects of n-3 and n-6 polyunsaturated fatty acid alimentation on murine peritoneal macrophage phospholipids. Mice were fed complete diets supplemented with either corn oil predominantly containing 18:2n-6, borage oil containing 18:2n-6 and 18:3n-6, fish/corn oil mixture containing 18:2n-6, 20:5n-3 and 22:6n- 3, or fish/borage oil mixture containing 18:2n-6, 18:3n-6, 20:5n-3 and 22:6n-3. After two weeks, the fatty acid levels of glycerophosphoserines (GPS), glycerophosphoinositols (GPI), sphingomyelin (SPH), and of the glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) phospholipid subclasses were determined. We found that mouse peritoneal macrophage GPC contain primarily 1-O-alkyl-2-acyl (range for the dietary groups, 24.6-30.5 mol %) and 1,2-diacyl (63.2-67.2 mol %), and that GPE contains 1-O- alk-1′-enyl-2-acyl (40.9-47.4 mol %) and 1,2-diacyl (44.2-51.2 mol %) subclasses. In general, fish oil feeding increased macrophage 20:5n- 3, 22:5n-3 and 22:6n-3 levels while simultaneously reducing 20:4n-6 in GPS, GPI, GPE and GPC subclasses except for 1-O-alk-1′-enyl-2-acyl GPC. Administration of 18:3n-6 rich diets (borage and fish/borage mixture) resulted in the accumulation of 20:3n-6 (2-carbon elongation product of 18:3n-6) in most phospholipids. In general, the novel combination of dietary 18:3n-6 and n-3 PUFA produced the highest 20:3n-6/20:4n-6 phospholipid fatty acid ratios. This study demonstrates that marked differences in the responses of macrophage phospholipid classes and subclasses exist following dietary manipulation.


Reference 37

Chapkin RS Somers SD Erickson KL

Dietary manipulation of macrophage phospholipid classes: selective increase of dihomogammalinolenic acid.

In: Lipids (1988 Aug) 23(8):766-70

Because alterations in the dietary content of fatty acids are an important method for modulating macrophage eicosanoid production, we have quantitated the levels of n-6 and n-3 polyunsaturated fatty acids in peritoneal macrophage individual phospholipids from mice fed diets (3 wk) with either safflower oil (SAF), predominantly containing 18:2n-6, borage (BOR) containing 18:2n-6 and 18:3n-6, fish (MFO) containing 20:5n-3 and 22:6n-3, and borage/fish mixture (MIX) containing 18:2n-6, 18:3n-6, 20:5n-3 and 22:6n-3. Dietary n-3 fatty acids were readily incorporated into macrophage phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI). The increase in n-3 fatty acid levels was accompanied by a decrease in the absolute levels of 18:2n-6, 20:4n-6 and 22:4n-6 in PC, PE and PS. Interestingly, PI 20:4n-6 levels were not significantly lowered (P greater than 0.05) in MIX and MFO macrophages relative to SAF and BOR. These data demonstrate the unique ability of this phospholipid to selectively maintain its 20:4n- 6 levels. In BOR and MIX animals, 20:3n-6 levels were significantly increased (P less than 0.05) in all phospholipids relative to SAF and MFO. The combination of borage and fish oils (MIX diet) produced the highest 20:3n-6/20:4n-6 ratio in all phospholipids. These data show that the macrophage eicosanoid precursor levels of 20:3n-6, 20:4n-6 and n-3 acids can be selectively manipulated through the use of specific dietary regimens. This is noteworthy because an increase in phospholipid levels of 20:3n-6 and 20:5n-3, while concomitantly reducing 20:4n-6, may have therapeutic potential in treating inflammatory disorders.


Reference 38

Chapkin RS Somers SD Schumacher L Erickson KL

Fatty acid composition of macrophage phospholipids in mice fed fish or borage oil.

In: Lipids (1988 Apr) 23(4):380-3

The polyunsaturated fatty acid (PUFA) composition of murine peritoneal macrophage phospholipids was dramatically altered in vivo following the four-wk feeding of specific dietary oils. Fish oil (containing 20:5n-3 and 22:6n-3) feeding significantly increased macrophage 20:5n-3, 22:5n-3, and 22:6n-3 (P less than 0.05), while borage oil (containing 18:2n-6 and 18:3n-6) increased (P less than 0.05) the macrophage 20:3n-6/20:4n-6 ratio, relative to safflower oil (containing 18:2n-6) and hydrogenated coconut oil (containing 12:0)- fed animals. The macrophage phospholipid PUFA profiles were compared with those of the liver, lung and spleen. The significance of the PUFA alterations is discussed.