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Adesina A Jonathan / JPBMS, 2012, 20 (08) Available online at www.jpbms.info Review article JPBMS ISSN NO- 2230 – 7885 CODEN JPBSCT NLM Title: J Pharm Biomed Sci. JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL SCIENCES Classification, Biosynthesis and health implications of n-3 and n-6 PUFAs * Adesina Adeolu Jonathan Department of Chemistry. Ekiti State University,PMB 5363, Ado Ekiti. Nigeria. Abstract: The world wide diversity of dietary intakes of n-6 and n-3 fatty acids influences tissue compositions of n-3 long chain fatty acids: eicosapentaenoic, docosapentaenoic and docosahexaenoic acids and risk of cardiovascular and mental illness. Linoleic acid (LA) and alpha- linolenic acid (ALA) belong to the n-6 (Omega -6) and n-3 (Omega- 3) series of PUFA (polyunsaturated fatty acids) respectively. They are defined ‘’ essential’’ fatty acids since they are not synthesized in the human body and are mostly obtained from the diet. Food sources of ALA and LA are mostly vegetable oils, cereals and walnuts. Recent advances in chromatographic identification of CLA isomers, combined with interest in their possible properties in promoting human health (e.g., cancer prevention, decreased atherosclerosis, improved immune response) and animal performance (e.g., body composition, regulation of milk fat synthesis, milk production further promotes the interest in research on PUFA . This review deeply probes into the chemistry, health benefits, and risks of n-3 and n-6 PUFA linking their biological functions to biochemistry and metabolism as well as revising the important cardioprotective effects of n-3in the secondary prevention of sudden cardiac death due to arrhythmias. Keywords: classification, biosynthesis, health implications, n-3 and n-6 PUFAs. Introduction: Low-fat foods have frequently been advocated for people attempting to diet. Some people on diets to lose weight have discovered that they can satisfy their appetite with fewer calories by eating protein and carbohydrate instead of fat. Losing weight not only makes a person look good, it can reduce the danger of getting heart disease, diabetes and cancer [1]. But the health hazards and benefits of fats, carbohydrates and proteins and their effectiveness for diets and dieting - depend greatly on the type of fat, carbohydrate and protein. Dietary fat by itself, not just the body fat it produces, can be a health hazard. A recent study has shown that reducing dietary fat from 36% of total calories to 26% of total calories can significantly lower blood pressure within 8 weeks [2]. Saturated fat in the diet can increase the risk of heart disease from atherosclerosis (fatty plaques on blood vessel walls) by raising blood cholesterol. Unsaturated fat is more likely to form free radicals by lipid peroxidation — which can lead to cancer and may accelerate aging. Therefore, both saturated and unsaturated fat can have health hazards. But every cell membrane in the body contains fat, and some of those fats cannot by synthesized — making it essential to obtain these fats from diet. Some nutritionists have recommended substituting monounsaturated and poly-unsaturated fats for saturated fats, but another recommendation is to substitute protein and carbohydrate calories for fat calories [2,3]. Fats (especially animal fats) are the primary vehicle by which pesticides enter the body. Some people might conclude that it would be a good idea to eliminate all fat from the diet. But eliminating all fat is not a good idea. Current nutrition recommendations are directed to prevent degenerative pathologies, such as cardiovascular 1 diseases and cancer [3]. In fact, inhibition or promotion of atherogenesis can be influenced by a specific dietary pattern and, similarly, factors such as food and nutrition may reduce the incidence of different types of cancers [85]. The current guidelines formulated by the most authoritative nutritional organizations invite the population worldwide to consume no more than 7–10% of calories from saturated fatty acids; less than 300 mg/day of cholesterol; keep trans fatty acids consumption as low as possible. In Western countries, the total fat intake should be in the range of 25–35%of total daily calories, with most fats coming from sources heavily endowed with monounsaturated and polyunsaturated fatty acids (MUFA and PUFA, respectively), such as fish, nuts, and vegetable oils[3]. LA and ALA are members of two well-known classes of PUFA, namely n - 6 (omega-6) and n - 3 (omega-3) series. From a biochemical point of view, both have 18 carbon atoms in their acyl chain presenting two (LA) or three (ALA) C- C double bonds. The position of the first unsaturation counting from the methyl end of the fatty acid, the so-called omega-C, generated the name of the two different classes. From a nutritional point of view, LA and ALA are commonly considered as ‘‘essential’’ fatty acids (EFA), since they are not synthesized in the human body and are mostly obtained from the diet. Unsaturated fatty acids include also the n - 9 series, derived from oleic acid (OA, 18:1) and the n 7 series, derived from palmitoleic acid (16:1), which are not essential [4,5]. Dietary sources of n -6 FAs are abundantly present in liquid vegetable oils, including soybean, corn, sunflower, safflower oil, cotton seed oils, while linseed and canola oils are rich in n 3 FAs (Table 1) [3,6]. Journal of Pharmaceutical and Biomedical Sciences ©(JPBMS), Vol. 20, Issue 20 Adesina A Jonathan / JPBMS, 2012, 20 (08) Table 1. Dietary sources of selected EFAs and PUFAs Product LA (mg/100g) ALA (mg/100g AA (mg/100g) EPA+DHA n-6 FAs rich foods Corn oil 50000 900 Cottonseed oil 47800 1000 Peanut oil 23900 Soybean oil 53400 7600 Sunflower oil 60200 500 Safflower oil 74000 470 Margarine 17600 1900 Lard 8600 1000 Chicken egg 3800 220 Bacon 6080 250 250 130 Ham 2480 160 Soya bean 8650 1000 1070 Maize 1630 40 Almond 9860 260 Brazil nut 24900 Peanut 13900 530 Walnut 34100 6800 Canola oil 19100 8600 Linseed oil 13400 55300 Herring 150 61.66 36.66 1700 Salmon 440 550 300 1200 Trout 74 30 500 Tuna 260 270 280 400 Cod 4 2 2 300 590 n-3 FAs rich foods Eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) belong to the n -3 series of FAs and are abundantly present in fish and shellfish. Fish such as salmon, trout and herring are higher in EPA and DHA than others (e.g., cod, haddock and catfish); in fact, fish-oil supplements typically contain 30–50% of n -3 FAs (Table 1). However, quantities vary among species and within a species according to environmental variables such as diet and whether fish are wild or farm-raised. As an example, farm raised catfish tend to have less EPA/DHA than do wild catfish, whereas salmon and trout contain similar amounts in the two different growing processes [3,7,45]. It is worthwhile to note that the limited amounts of n-3 FAs present in meats became nutritionally important considering the large quantities of beef, pork, poultry consumed in Western diets [3,6,8]. The essential fatty acid a-linolenic acid (18:3n-3, ALA) is the predominant n-3 fatty acid in the Western diet. Estimated ALA consumption is approximately 1.5 g per day, which is about 10-fold lower than linoleic acid (18:2n6), the equivalent n-6 essential fatty acid [8]. Whether the dietary essentiality of ALA reflects the activity of ALA itself or of longer-chain, more unsaturated fatty acids synthesized from ALA, including eicosapentaenoic acid (20:5n-3, EPA) and docosahexaenoic acid (22:6n-3, DHA), remains a matter for debate. The concentration of a-LNA in cell membranes and blood lipids in healthy adult humans is typically less than 0.5% of total fatty acids, which suggests that the ALA content of these lipid pools is likely to have a 2 limited influence on biological function. In contrast, the longer-chain more unsaturated n-3 fatty acids docosapentaenoic acid (22:5n-3, DPA) and DHA, and to a lesser extent EPA, are present in substantially greater amounts in cell membranes and in the circulation. In particular, DHA accounts for about 20–50% of fatty acids in the brain and in the retina [3,6,8]. Perhaps the strongest evidence in support of the suggestion that the principal biological role of ALA is as a substrate for synthesis of longer chain polyunsaturated fatty acids (PUFAs) comes from studies in animal models, which show that reduced maternal dietary ALA intake during pregnancy adversely affects retinal function in the offspring. This is due to a reduction in accumulation of DHA into photoreceptor cells and reflects impaired rhodopsin activity. The last two decades have seen a proliferation of studies on the cardioprotective effects of EFA/PUFA, especially the n 3 series. The purpose of this review therefore is to assess the chemistry as well as the beneficial and detrimental effects of n-3 and n-6 PUFAs. Essential fatty acids in the diet The primary source of omega−6 fatty acids in the diet is linoleic acid from the oils of seeds and grains. Sunflower, safflower and corn oil are particularly rich sources of linoleic acid, which is at the root of the omega−6 fatty-acid family. Evening primrose oil and borage oil are high not only in linoleic acid, but the omega−6 derivative gammalinolenic acid (GLA). Avocado is 15-20% oil — mainly Journal of Pharmaceutical and Biomedical Sciences© (JPBMS), Vol. 20, Issue 20 Adesina A Jonathan / JPBMS, 2012, 20 (08) monosaturated, but also high in linoleic acid. (Avocado has the highest fat content and the highest fiber content — soluble as well as insoluble — of any fruit). A more fairly comprehensive list is presented in Table 2. Given below: Table 2.Fat constituents as % of total fat for selected foods. Courtesy/Sources: [3, 86] General classification of some common n-3 and n-6 PUFAs Polyunsaturated fatty acids are fatty acids that contain more than one double bond in their backbone. This class includes many important compounds, such as essential fatty acids and those that give drying oils their characteristic property. These fatty acids have 2 or more cis double bonds that are separated from each other by a single methylene group. (This form is also sometimes called a divinylmethane pattern.) [9]. The list of PUFAs comprising both n-3 and n-6 groups are presented in Table 3. Below: Table 3. List of common n-3 and n-6 PUFAs Omega-3 fatty acids Common name Lipid name Chemical name Hexadecatrienoic acid (HTA) 16:3 (n-3) all-cis 7,10,13-hexadecatrienoic acid Alpha-linolenic acid (ALA) 18:3 (n-3) all-cis-9,12,15-octadecatrienoic acid Stearidonic acid (SDA) 18:4 (n-3) all-cis-6,9,12,15,-octadecatetraenoic acid Eicosatrienoic acid (ETE) 20:3 (n-3) all-cis-11,14,17-eicosatrienoic acid Eicosatetraenoic acid (ETA) 20:4 (n-3) all-cis-8,11,14,17-eicosatetraenoic acid Eicosapentaenoic acid (EPA, Timnodonic acid) 20:5 (n-3) all-cis-5,8,11,14,17-eicosapentaenoic acid Heneicosapentaenoic acid (HPA) 21:5 (n-3) all-cis-6,9,12,15,18-heneicosapentaenoic acid Docosapentaenoic acid (DPA, Clupanodonic acid) 22:5 (n-3) all-cis-7,10,13,16,19-docosapentaenoic acid Docosahexaenoic acid (DHA, Cervonic acid) 22:6 (n-3) all-cis-4,7,10,13,16,19-docosahexaenoic acid Tetracosapentaenoic acid 24:5 (n-3) all-cis-9,12,15,18,21-tetracosapentaenoic acid Tetracosahexaenoic acid (Nisinic acid) 24:6 (n-3) all-cis-6,9,12,15,18,21-tetracosahexaenoic acid 3 Journal of Pharmaceutical and Biomedical Sciences© (JPBMS), Vol. 20, Issue 20 Adesina A Jonathan / JPBMS, 2012, 20 (08) Common name Lipid name Chemical name Linoleic acid 18:2 (n-6) all-cis-9,12-octadecadienoic acid Gamma-linolenic acid (GLA) 18:3 (n-6) all-cis-6,9,12-octadecatrienoic acid Eicosadienoic acid 20:2 (n-6) all-cis-11,14-eicosadienoic acid Dihomo-gamma-linolenic acid (DGLA) 20:3 (n-6) all-cis-8,11,14-eicosatrienoic acid Arachidonic acid (AA) 20:4 (n-6) all-cis-5,8,11,14-eicosatetraenoic acid Docosadienoic acid 22:2 (n-6) all-cis-13,16-docosadienoic acid Adrenic acid 22:4 (n-6) all-cis-7,10,13,16-docosatetraenoic acid Docosapentaenoic acid (Osbond acid) 22:5 (n-6) all-cis-4,7,10,13,16-docosapentaenoic acid Tetracosatetraenoic acid 24:4 (n-6) all-cis-9,12,15,18-tetracosatetraenoic acid Tetracosapentaenoic acid 24:5 (n-6) all-cis-6,9,12,15,18-tetracosapentaenoic acid Sources: [9,10] Fig 1. Biosynthesis of long-chain fatty acids Biosynthesis of some PUFAs The pathway for conversion of a-LNA to EPA, DPA and DHA has been described in rat liver [8]. All reactions occur at the endoplasmic reticulum, with the exception of the final reaction to form DHA. The rate limiting reaction is the initial desaturation at the 6 position by Δ 6-desaturase, followed by addition of C2 and desaturation at the Δ 5 position to form EPA (Fig.1). Fig. 1 shows the most significant steps transforming LA and ALA to their higher unsaturated derivatives (AA, EPA, DHA) by the activities of consecutive desaturation and elongation reactions. One of the key enzymes in the metabolism of EFA/ PUFA is d-6-d which recognizes and metabolizes LA and ALA producing GLA, and octadecatetraenoic (stearidonic) acids, respectively. The affinity of d-6-d for EFAs is different; in fact, the concentration of ALA required to inhibit GLA formation by 50% is about 10 times the concentration of the substrate (LA) [3], suggesting that in the presence of higher concentration of LA, such as occurs in a living system, the pathway leading to AA is preferred . 4 After desaturation by d-6-d, a cycle of elongation and desaturation by d-5-d (delta-5-desaturase) generates AA (20:4n -6) and EPA (20:5n -3) starting from LA and ALA, respectively (Fig. 1). The obvious formation of the 22:5n - 6 and 22:6n-3 series by a further step of elongation and desaturation by a hypothetical d-4-d (delta-4-desaturase) has been a matter of controversy, since this enzyme has been only identified in microalgae. In mammals, two cycles of elongations and one of desaturation by d-6-d form tetracosahexaenoic acid (24:6n- 3; Fig. 1) and tetracosapentaenoic acid (24:5n - 6). These two PUFAs are transferred from the endoplasmic reticulum (ER) to peroxisomes (the so-called Sprecher’s shunt), where they undergo beta-oxidation to generate DHA (22:6n -3; Fig. 1) and docosapentaenoic acid (22:5n-6, also called osbond acid) which both return to the ER. ALA deficiency reduced DHA and enhanced osbond acid levels in tissue membranes; therefore, it is considered a functional indicator of DHA status. Mammals can also convert DHA into EPA, but human bodies struggle to make this conversion which is not a very efficient process. Retroconversion of supplemental DHA to EPA was Journal of Pharmaceutical and Biomedical Sciences© (JPBMS), Vol. 20, Issue 20 Adesina A Jonathan / JPBMS, 2012, 20 (08) significantly greater in an EFA-deficient cell line (EPCEFAD) [11]. As described earlier, when present in adequate amounts, linoleic acid is converted to arachidonic acid through a multi-step process involving Δ6 and Δ5 desaturases (see Fig. 1.); however, in the absence of linoleic acid, Δ6 and Δ5 desaturases convert oleic acid to eicosatrienoic acid. The increase in eicosatrienoic acid concentration, which occurs in the absence of n-6 fatty acids or the combined absence of n-6 and n-3 fatty acids, led Holman (1960) to define a plasma triene:tetraene ratio of greater than 0.4 as evidence of essential fatty acid deficiency. More recently, a lower threshold of greater than 0.2 has been suggested [12-14] because the average ratio was found to be 0.1 ± 0.08 (standard deviation) in populations of normal n-6 fatty acid status. Optimal plasma or tissue lipid concentrations of linoleic acid, arachidonic acid, and other n-6 fatty acids or the ratios of certain n-6:n-3 fatty acids have not been established. Interaction of n-6 and n-3 Fatty Acid Metabolism The n-6 and n-3 unsaturated fatty acids are believed to be desaturated and elongated using the same series of desaturase and elongase enzymes (see Fig 1.). The ratelimiting steps are the desaturases, rather than the elongase, enzymes. In vitro, the Δ6 desaturase shows clear substrate preference in the following order: α-linolenic acid > linoleic acid > oleic acid [15]. In addition, the formation of docosahexaenoic acid (DHA) from tetracosapentenoic acid (24:5n-3) involves a Δ6 desaturation to 24:6n-3 and then β-oxidation to yield 22:6n-3 (DHA) [16]. It is not known if these are the Δ6 desaturases that are responsible for metabolism of linoleic acid and α-linolenic acid or a different enzyme [17]. Many studies, primarily in laboratory animals, have provided evidence that the balance of linoleic and α-linolenic acid is important in determining the amounts of arachidonic acid, eicosapentaenoic acid (EPA), and DHA in tissue lipids. An inappropriate ratio may involve too high an intake of either linoleic acid or α-linolenic acid, too little of one fatty acid, or a combination leading to an imbalance between the two series. The provision of preformed carbon chain n-6 and n3 fatty acids results in rapid incorporation into tissue lipids. Thus, the linoleic:α-linolenic acid ratio is likely to be of most importance for diets that are very low in or devoid of arachidonic acid, EPA, and DHA. The importance of the dietary linoleic:α-linolenic acid ratio for diets rich in arachidonic acid, EPA, and DHA is not known. Arachidonic acid is important for normal growth in rats [18]. Later in life, risk of certain diseases may be altered by arachidonic acid and arachidonic acid-derived eicosanoids. Consequently, the desirable range of n-6:n-3 fatty acids may differ with life stage. The regulation of n-6 and n-3 fatty acid metabolism is complex as the conversion of linoleic acid to arachidonic acid is inhibited by EPA andDHA in humans, as well as arachidonic acid, α-linolenic acid, and linoleicacid itself [19-23]. Similarly, stable isotope studies have shown that increased intakes of α-linolenic acid result in decreased conversion of linoleic acid to its metabolites, and the amounts metabolized to longerchain metabolites is inversely related to the amount oxidized [24]. Unfortunately, very few studies are available on the rates of formation of arachidonic acid and DHA from their precursors in humans fed diets differing in linoleic acid and α-linolenic acid content, and with or without controlled amounts of 5 arachidonic acid, EPA, and DHA. Arachidonic acid is a precursor to a number of eicsanoids (e.g., thromboxane A2, prostacylcin, and leukotriene B4). These eicosanoids have been shown to have beneficial and adverse effects in the onset of platelet aggregation, hemodynamics, and coronary vascular tone. EPA has been shown to compete with the biosynthesis of n-6 eicosanoids and is the precursor of several n-3 eicosanoids (e.g., thromboxane A3, prostaglandin I3, and leukotriene B5), resulting in a less thrombotic and atherogenic state [25]. n-6:n-3 Polyunsaturated Fatty Acid Ratio Jensen and coworkers [58] reported that infants fed formulas containing a linoleic acid:α-linolenic acid ratio of 4.8:1 had lower arachidonic acid concentrations and impaired growth compared to infants fed formulas containing ratios of 9.7:1 or higher. More recent, large clinical trials with infants fed formulas providing linoleic acid:α-linolenic acid ratios of 5:1 to 10:1 found no evidence of reduced growth or other problems that could be attributed to decreased arachidonic acid concentrations [26,27,84]. Clark and coworkers [28] concluded that intake ratios less than 4:1 were likely to result in fatty acid profiles markedly different from those from infants fed human milk. Based on the limited studies, the linoleic acid:α-linolenic acid or total n-3:n-6 fatty acids ratios of 5:1 to 10:1, 5:1 to 15:1, and 6:1 to 16:1 have been recommended for infant formulas [29-31]. In adult rats it has been determined that a linoleic acid:α-linolenic acid ratio of 8:1 was optimal in maintaining normal-tissue fatty acid concentrations [32]. Increasing the intake of linoleic acid from 15 to 30 g/d, with an increase in the linoleic:αlinolenic acid ratio from 8:1 to 30:1, resulted in a 40 to 54 percent decreased conversion of linoleic acid and αlinolenic acid to their metabolites in healthy men [20]. Clinical studies with patients supported by total parenteral nutrition found resolution of signs of deficiency when a parenteral lipid containing a linoleic acid:α-linolenic acid ratio of 6:1 was provided [12]. Clinical and epidemiological studies have addressed the n6:n-3 fatty acid ratio, focusing on beneficial effects on risk of certain diseases associated with higher intakes of the n3 fatty acids EPA and DHA, as reviewed in [3]. The specific importance of the ratio in these studies cannot be assessed because the decreased ratio is secondary to an increased intake of fish or EPA and DHA from supplements. For example, low rates of heart disease in Japan, compared with the United States, have been attributed in part to a total n-6:n-3 fatty acid ratio of 4:1 [33], with about 5 percent energy as linoleic acid, 0.6 percent energy from α-linolenic acid, and 2 percent energy from EPA+DHA in Japan, compare with intakes of 6 percent energy from linoleic acid, 0.7 percent energy from α-linolenic acid, and less than 0.1 percent energy from EPA+DHA in the United States [33]. Similarly, an inverse association between the dietary total n-6:n-3 fatty acid ratio and cardiovascular disease, cancer, and all-cause mortality [34], as well as between fish intake and coronary heart disease mortality [35,36], have been reported. In other studies, however, no differences were found in coronary heart disease risk factors when a diet containing a total n-6:n-3 ratio of 4:1 compared to 1:1 was consumed [37], or in thrombotic conditions with a diet containing a total n-6:n-3 ratio of 3.3:1 compared with 10:1 [38]. Hu and coworkers [39] observed a weak relationship between the n-6:n-3 ratio and fatal ischemic heart disease Journal of Pharmaceutical and Biomedical Sciences© (JPBMS), Vol. 20, Issue 20 Adesina A Jonathan / JPBMS, 2012, 20 (08) since both α-linolenic acid and linoleic acid were inversely related to risk. Based on the limited studies in animals, children, and adults, a reasonable linoleic:α-linolenic acid ratio of 5:1 to 10:1 has been recommended for adults [40]. Benefits of EFAs / PUFAs The biological effects of the ω-3 and ω-6 fatty acids are mediated by their mutual interactions, in the body, essential fatty acids serve multiple functions. In each of these, the balance between dietary ω-3 and ω-6 strongly affects function. They are modified to make: the classic eicosanoids (affecting inflammation and many other cellular functions), the endocannabinoids (affecting mood, behavior and inflammation), the lipoxins from ω-6 EFAs and resolvins from ω-3 (in the presence of aspirin, down regulating inflammation.), the isofurans, neurofurans, isoprostanes, hepoxilins, epoxyeicosatrienoic acids (EETs) and Neuroprotectin D. They form lipid rafts (affecting cellular signaling) [41]. They act on DNA (activating or inhibiting transcription factors such as NF-κB, which is linked to pro-inflammatory cytokine production [42]. Amelioration of pathological conditions, cell viability and inflammation Although the terms ‘‘PUFA’’ and ‘‘EFA’’ are not synonymous (only LA and ALA are essential from a biochemical and nutritional point of view), they are often used interchangeably since many biological functions of EFAs are exerted by EFA derived PUFAs, such as arachidonic acid (AA, 20:4n -6), DHA, EPA [3,4]. Deficits in n - 6 EFAs/PUFAs were correlated with the severity of atopic dermatitis by affecting skin barrier function and cutaneous inflammation, which may be ameliorated by diets with evening primrose or borage oil (vegetable oils that contain gamma-linolenic acid (GLA)) [3,43]. It is still debated which of the different biological functions of n -6 PUFAs are predominant in this pathology. Essentiality of ALA and its metabolites are still a matter of opinion. In many cases, n _ 3 and n -6 FAs can compensate each other’s function in ameliorating pathological conditions, such as growth retardation. In other situations, the biological activity of the n -3 series is more specific. DHA, in fact, is required in the nervous system for optimal neuronal and retinal function and influences signaling events which are vital for neuronal survival and differentiation [3,6,44]. Whether EFAs/PUFAs are essential for cell viability remains elusive. In fact, a recent work demonstrated that deletion of FADS2 (Fatty acid desaturase) gene in mouse, abolished the expression of delta-6-desaturase (d-6-d), a key enzyme in the enzymatic cascade of EFA/PUFA biosynthesis (see below). However, lack of PUFAs did not impair the normal viability and lifespan of male and female mice [80]. The concentration of a-LNA in cell membranes and blood lipids in healthy adult humans is typically less than 0.5% of total fatty acids, which suggests that the A LA content of these lipid pools is likely to have a limited influence on biological function. In contrast, the longer-chain more unsaturated n3 fatty acids docosapentaenoic acid (22:5n-3, DPA) and DHA, and to a lesser extent EPA, are present in substantially greater amounts in cell membranes and in the circulation. In particular, DHA accounts for about 20–50% of fatty acids in the brain and in the retina [3,7]. Perhaps the strongest evidence in support of the suggestion that the principal biological role of ALA is as a substrate for 6 synthesis of longer chain polyunsaturated fatty acids (PUFAs) comes from studies in animal models, which show that reduced maternal dietary ALA intake during pregnancy adversely affects retinal function in the offspring. This is due to a reduction in accumulation of DHA into photoreceptor cells and reflects impaired rhodopsin activity [8]. Effects of EFAs/ PUFAs in cardiovascular diseases The cardio-protective effects of n _ 3 FAs have long been recognized. The original observation is dated almost 50 years ago, when Hugh M. Sinclair published his observations on the negative effects of some EFA deficiency on CVD. He strengthened his hypothesis noting the low incidence of mortality rate from CHD (coronary heart disease) in Greenland Eskimos, a population consuming a high fat diet, but rich in n- 3 FAs [3,46]. Late in the seventies, Sinclair’s group and others confirmed the positive association between the high dietary intake of EPA and DHA of Greenland Inuit and lower rate of death from acute myocardium infarction (MI) compared to a Danish population, although these two groups consumed similar amount of total fat (about 42% of total calories) and showed comparable level of blood cholesterol [47]. Similarly Japanese population eats more fish than North Americans and presents a lower rate of acute myocardial infarction, atherosclerosis and other ischemic pathologies [3]. Among the possible mechanisms that may contribute to the cardiovascular benefits of n - 3 FAs, their ability to decrease triglycerides and VLDL has been reported, with moderate rise in HDL, whereas n _ 6 FAs do not [3,47,48]. On the opposite, the GISSI study showed only a very small decrease in triglyceride concentrations and no clinically significant changes in cholesterol [49]. Overall, n _ 3 FAs do not seem to have a very significant effect neither in lowering blood lipids, nor fibrinolysis and plasminogen activator inhibitor-1 (reviewed in [50]), generating a paradox on their protective effects against CHD. More recent reviews analyzed the past and recent achievements in favor of the cardiovascular benefits of n -3 FAs [51,52]. It is worthwhile to note that the administration of ALA or ALA-containing food to replace fish or EPA/DHA for those who dislike or cannot eat fish do not modify the conclusions. In fact, two intervention trials, the Lyon Diet Heart Study [53] and the Indian Diet Heart Study [54], confirmed that an ALA rich diet may improve prognosis in patients with a first episode MI. However, in the former, the consumption of ALA (1.8 g/day) was associated with a Mediterranean style diet, leaving doubt that the reduction in sudden cardiac death could be due to other ingredients present in the diet. In the latter study, the increased consumption of vegetables rich in ALA was part of a lowfat diet (24–28% of the total calories). Also in this case, the interpretation of the result is based on the specific experimental design. Finally, in the Indian Experiment of Infarct Survival [3,81], fish oil capsules (1.08 g/day EPA plus 0.72 g/day DHA) and mustard seed oil (2.9 g/day ALA) behaved similarly in reducing total cardiac death and risk of cardiac arrhythmias in patients treated for 1 year starting 24 h after a first episode of MI. The molecular explanation for the anti-arrhythmic effects of n _ 3 FAs are still a matter of opinion and further studies are required to confirm or exclude the different hypothesis formulated. Human data are strongly supported by observational and interventional studies, but lack a mechanistic Journal of Pharmaceutical and Biomedical Sciences© (JPBMS), Vol. 20, Issue 20 Adesina A Jonathan / JPBMS, 2012, 20 (08) demonstration from a molecular point of view. Data obtained on animal models and cultured cardiomyocytes suggest that the anti-arrhythmic effects of n -3 FAs are due to the ability of ALA and EPA/DHA to influence the activity of myocyte sarcolemma ion channels (sodium and L-type calcium). In fact, these EFAs/PUFAs are able to: (i) increase the threshold of ventricular fibrillation; (ii) increase heart rate variability; (iii) reduce ischemic damage [47,55,56]. A remarkable aspect of the n -3 FA treatments is that they are well tolerated and have no serious side effects during the trials. Following a prolonged supplementation, bleeding complications may have been expected, which was never reported in the literature [57]. More controversial is the role of n-6 FAs in cardiovascular disease prevention. Earlier studies have shown that LA improves lipid profile by lowering total cholesterol and LDL cholesterol and slightly increasing HDL-cholesterol [51], whereas others seem to contradict these conclusions [47,50,58]. More recently, the ability of n _ 6 FAs to increase oxidation susceptibility of lipoproteins (LDL and VLDL) has been evoked as a possible mechanism to explain adverse effects of a diet high in six FAs against CVD [59]. However, n -3 FAs contains even more unsaturations. In fact, fish oil FAs adversely raise the susceptibility of LDL to copper-induced and macrophage-mediated oxidation [3]. Perhaps, this paradox diminishes the force of the oxidation argument in establishing the role of EFAs/PUFAs in CVD. It is also important to note that almost all the PUFAs in the Human diet are EFAs. Essential fatty acids plays an important role in the life and death of cardiac cells [3,56]. Treatment for depression Research suggests that high intakes of fish and omega-3 fatty acids are linked to decreased rates of major depression. Omega-3 fatty acids, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are important for enzymatic pathways required to metabolize long-chain polyunsaturated fatty acids (PUFAs). Low plasma concentrations of DHA predict low concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA). It is found that low concentrations of 5-HIAA in the brain is associated with depression and suicide [60]. There are high concentrations of DHA in synaptic membranes of the brain. This is critical for synaptic transmission and membrane fluidity [3]. The omega-6 fatty acid to omega-3 fatty acid ratio is important to avoid imbalance of membrane fluidity. Membrane fluidity affects function of enzymes such as adenylate cyclase and ion channels such as calcium, potassium, and sodium, which in turn affects receptor numbers and functioning, as well as serotonin neurotransmitter levels. It is evident that western diets are deficient in omega-3 and excessive in omega-6, and balancing of this ratio would confer numerous health benefits [61]. Although further research is needed, there are studies providing evidence for the role of omega-3 fatty acids in the treatment of depression during the perinatal period. Correlations have been found between depression and low levels of omega-3 fatty acids, and treatment with omega-3 supplementation shows benefit for depression as well as other mood disorders. Research also suggests that supplementation is beneficial for healthy infant development [60]. Problems associated with deficiencies of PUFAs (n-3 and n-6) Dangers of Polyunsaturates 7 The irony is that these trends have persisted concurrently with revelations about the dangers of polyunsaturates. Because polyunsaturates are highly subject to rancidity, they increase the body's need for vitamin E and other antioxidants. Excess consumption of vegetable oils is especially damaging to the reproductive organs and the lungs—both of which are sites for huge increases in cancer in the US. In test animals, diets high in polyunsaturates from vegetable oils inhibit the ability to learn, especially under conditions of stress; they are toxic to the liver; they compromise the integrity of the immune system; they depress the mental and physical growth of infants; they increase levels of uric acid in the blood; they cause abnormal fatty acid profiles in the adipose tissues; they have been linked to mental decline and chromosomal damage; they accelerate aging. Excess consumption of polyunsaturates is associated with increasing rates of cancer, heart disease and weight gain; excess use of commercial vegetable oils interferes with the production of prostaglandins leading to an array of complaints ranging from autoimmune disease to PMS. Disruption of prostaglandin production leads to an increased tendency to form blood clots, and hence myocardial infarction, which has reached epidemic levels in America [62]. Vegetable oils are more toxic when heated. One study reported that polyunsaturates turn to varnish in the intestines. A study by a plastic surgeon found that women who consumed mostly vegetable oils had far more wrinkles than those who used traditional animal fats. A 1994 study appearing in the Lancet showed that almost three quarters of the fat in artery clogs is unsaturated. The "artery clogging" fats are not animal fats but vegetable oils [63]. Those who have most actively promoted the use of polyunsaturated vegetable oils as part of a Prudent Diet are well aware of their dangers. In 1971, William B. Kannel, former director of the Framingham study, warned against including too many polyunsaturates in the diet. A year earlier, Dr. William Connor of the American Heart Association issued a similar warning, and Frederick Stare reviewed an article which reported that the use of polyunsaturated oils caused an increase in breast tumors. And Kritchevsky, way back in 1969, discovered that the use of corn oil caused an increase in atherosclerosis [64]. As for the trans fats, produced in vegetable oils when they are partially hydrogenated, the results that are now in the literature more than justify concerns of early investigators about the relation between trans fats and both heart disease and cancer. The research group at the University of Maryland found that trans fatty acids not only alter enzymes that neutralize carcinogens, and increase enzymes that potentiate carcinogens, but also depress milk fat production in nursing mothers and decrease insulin binding [65]. In other words, trans fatty acids in the diet interfere with the ability of new mothers to nurse successfully and increase the likelihood of developing diabetes. Unpublished work indicates that trans fats contribute to osteoporosis. Hanis, a Czechoslovakian researcher, found that trans consumption decreased testosterone, caused the production of abnormal sperm and altered gestation [3]. Koletzko, a German pediatric researcher found that excess trans consumption in pregnant mothers predisposed them to low birth weight babies [3]. Trans consumption interferes with the body's use of omega-3 fatty acids found in fish oils, grains and Journal of Pharmaceutical and Biomedical Sciences© (JPBMS), Vol. 20, Issue 20 Adesina A Jonathan / JPBMS, 2012, 20 (08) green vegetables, leading to impaired prostaglandin production. George Mann confirmed that trans consumption increases the incidence of heart disease [3]. In 1995, European researchers found a positive correlation between breast cancer rates and trans consumption [3,4,83]. n-3 Polyunsaturated Fatty Acids Tissue levels of arachidonic acid, as well as the amounts of arachidonic acid and EPA- derived eicosanoids that are formed, have important effects on many physiological processes (e.g., platelet aggregation, vessel wall constriction, and immune cell function) via the biosynthesis of eicosanoids. Thus, the amount of n-3 fatty acids and their effects on arachidonic acid metabolism are relevant to many chronic diseases. EPA also appears to have specific effects on fatty acid metabolism, resulting in inhibition of hepatic triacylglycerol synthesis and VLDL secretion [66,67]. DHA, on the other hand, is highly enriched in specific phospholipids of the retina and nonmyelin membranes of the nervous system. Studies in rodents and nonhuman primates have consistently demonstrated that prolonged feeding with diets containing very low amounts of a-linolenic acid result in reductions of visual acuity thresholds and electroretinogram A and B wave recordings, which were prevented when a-linolenic acid was included in the diet. A variety of changes in learning behaviors in animals fed a-linolenic acid deficient diets have also been reported [68]. These studies have involved feeding oils such as safflower oil, which contains less than 0.1 percent a-linolenic acid and is high in linoleic acid, as the sole source of fat for prolonged periods. The reduction in visual function is accompanied by decreased brain and retina DHA with an increase in docosapentaenoic acid (DPA, 22:5n-6). The compensatory increase in 22 carbon chain n-6 fatty acids results in maintenance of the total amount of n-6 and n-3 polyunsaturated fatty acids in neural tissue. DPA is formed from linoleic acid by similar desaturation and elongation steps used in the synthesis of DHA from a-linolenic acid. However, a-linolenic acid is clearly handled differently from linoleic acid. For example, rates of a-oxidation of a-linolenic acid are much higher than for linoleic acid [69]. This may suggest that immaturity or reduced enzyme activity is unlikely to explain lower DHA in the brain of young animals fed diets with low amounts of a-linolenic acid, and that DHA has specific metabolic functions that cannot be accomplished by DPA despite its structural similarity. Stable isotope studies have shown that infants can convert linoleic acid to arachidonic acid and a-linolenic acid to DHA [70, 79], with the rate of conversion apparently higher in infants of younger gestational ages [70]. Unlike essential fatty acid deficiency (n-6 and n-3 fatty acids), plasma eicosatrienoic acid (20:3n9) remains within normal ranges and skin atrophy and scaly dermatitis are absent when the diet is deficient in only n-3 fatty acids. Tissue concentrations of 22-carbon chain n-6 fatty acids increase, and DHA concentration decreases with a prolonged dietary deficiency of n-3 fatty acids accompanied by adequate n-6 fatty acids. Currently, there are no accepted plasma n-3 fatty acid or n-3 fatty acid-derived eicosanoid concentrations for indicating impaired neural function or impaired health endpoints. n-6 Polyunsaturated Fatty Acids Certain polyunsaturated fatty acids were first identified as being essential in rats fed diets almost completely devoid 8 of fat [71]. Subsequently, studies in infants and children fed skimmed cow milk [72] and patients receiving parenteral nutrition without an adequate source of essential fatty acids, Holman et al. [12] demonstrated clinical symptoms of a deficiency in humans. Because adipose tissue lipids in free-living, healthy adults contain about 10 percent of total fatty acids as linoleic acid, biochemical and clinical signs of essential fatty acid deficiency do not appear during dietary fat restriction or malabsorption when they are accompanied by an energy deficit. In this situation, release of linoleic acid and small amounts of arachidonic acid from adipose tissue reserves may prevent development of essential fatty acid deficiency. However, during parenteral nutrition with dextrose solutions, insulin concentrations are high and mobilization of adipose tissue is prevented, resulting in development of the characteristic signs of essential fatty acid deficiency. Studies on patients given fatfree parenteral feeding have provided great insight into defining levels at which essential fatty acid deficiency may occur. Without intervention, these patients develop clinical signs of a deficiency in 2 to 4 weeks [13]. In rapidly growing infants, feeding with milk containing very low amounts of n-6 fatty acids results in characteristic signs of an essential fatty acid deficiency and elevated plasma triene:tetraene ratios (see “n-6:n-3 Polyunsaturated Fatty Acid Ratio”). When dietary essential fatty acid intake is inadequate or absorption is impaired, tissue concentrations of arachidonic acid decrease, inhibition of the desaturation of oleic acid is reduced, and synthesis of eicosatrienoic acid from oleic acid increases. The characteristic signs of deficiency attributed to the n-6 fatty acids are scaly skin rash, increased transepidermal water loss, reduced growth, and elevation of the plasma ratio of eicosatrienoic acid:arachidonic acid (20:3n-9:20:4n-6) to values greater than 0.4 [14,73]. Other studies have utilized a ratio of 0.2 as indicative of an essential fatty acid deficiency [13]. In addition to the clinical signs mentioned above, essential fatty acid deficiency in special populations has been linked to hematologic disturbances and diminished immune response [74]. Summary It seems likely that a combination of EPA and DHA reflecting nature may be optimally used in dietary supplementation to meet the n-3 long chain fatty acids intake goals [75]. Hibbeln et al. [75] further reported that a major source of dietary n-3 LCFA in his calculation was seafood containing both EPA and DHA in an average ratio of 1:2.3. High intakes of n-3 LCFAs may be associated with an increased risk of hemorrhagic stroke [76], but this risk may be offset by a decrease in thrombotic stroke and overall stroke mortality. A review of the literature on mental outcomes shows supplementation with a combination of both EPA and DHA likely to be more effective than use of either alone [75].the biological availability and activity of n-6 LCFAs in particular AA, are inversely related to n-3 FAs in tissue LCFAs. Greater compositions of EPA, DPA and DHA in membranes competitively lower the availability of AA for the production of eicosanoids [77]. The prevention of the formation of n-6 eicosanoids derived from AA with medications, including Cox-2 inhibitor, ibuprofen, acetaminophen and aspirin, constitutes a substantial proportion of pharmaceutical industry activity. The Journal of Pharmaceutical and Biomedical Sciences© (JPBMS), Vol. 20, Issue 20 Adesina A Jonathan / JPBMS, 2012, 20 (08) available tissue composition of AA can be lowered by reducing dietary intakes of the 18- carbon precursor LA. Finally, the most significant effect of EFAs/PUFAs in terms of human health is the n -3 FA protection in the secondary prevention of sudden cardiac death due to arrhythmias. Whether this indication can justify the application of a preventive program of dietary supplementation of n -3 FAs to the general population is still debatable. The dietary recommendations to increase the consumption of fish or n3 FA rich vegetables, for those who dislike fish, remain. Regardless, it is important to know the type, the size (larger fish can be subjected to methyl mercury contamination) and from where the fish have been procured. Dietary recommendations should distinguish between ALA and EPA/DHA and would be preferred to be made on amass basis (g/day) of n - 3 FAs to be consumed, strongly considering, at individual level, the intake of total energy, total fats and n -6 FA intake. The apparent absence of deleterious side effects of EFA/ PUFA treatments, accordingly to the Hippocratic aphorism: primum nil nocere, is neither a conclusive demonstration of their efficacy, nor a suggestion for an indiscriminate supplementation. It is necessary to intensify the scientific efforts in order to clarify many controversial aspects of EFA/PUFA consumption in order to make human diet healthier. In a series of investigations it was observed that the cytotoxic action of anticancer drugs can be augmented by PUFAs of both n-3 and n-6 series (GLA, arachidonic acid, EPA and DHA). In addition, these fatty acids could also enhance the cellular uptake of anticancer drugs by tumor cells and thus, are able to potentiate the anti-cancer actions of these drugs. PUFAs can not only kill the tumor cells but can also serve as sensitizing agents rendering various tumor cells responsive to the cytotoxic action of various anti-cancer drugs and lymphokines such as tumor necrosis factor. 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Visual acuity, erythrocyte fatty acid composition, and growth in term infants fed formulas with long chain polyunsaturated fatty acids for one year. Pediatr Res 41:1–10. 85. World Cancer Research Fund /American Institute for Cancer Research. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Washington, DC: AICR; 2007. 86. Scientificpsychic.com [Internet]. USA [cited 2012 may 9]. Available from: http://www.scientificpsychic.com/fitness/fattyacids1.h tml. Conflict of Interest:-None 11 Journal of Pharmaceutical and Biomedical Sciences© (JPBMS), Vol. 20, Issue 20 Adesina A Jonathan / JPBMS, 2012, 20 (08) Source of funding:- None Corresponding Author:ADESINA ADEOLU JONATHAN Department of Chemistry. Ekiti State University, PMB 5363, Ado Ekiti. Nigeria. Contact no:- +2348069258701. Quick Response code (QR-Code) for mobile user to access JPBMS website electronically. Website link:- www.jpbms.info 12 Journal of Pharmaceutical and Biomedical Sciences© (JPBMS), Vol. 20, Issue 20