Eicosapentaenoic Acid (EPA)

Overview

Eicosapentaenoic acid (EPA) is a member of the omega-3 family of fatty acids. Although EPA can be consumed directly by eating certain kinds of fish, it is also produced in the body from the conversion of alpha linolenic acid (ALA), also known as omega-3. The metabolic processes that convert omega-3 to EPA is accomplished by desaturase and elongase enzymes. Desaturase enzymes produce additional double bonds, while elongase enzymes add carbon atoms to make a longer fatty acid chain. The parent or precursor omega-3 molecule, alpha linolenic acid (ALA), is a long-chain fatty acid that contains 18 carbon atoms with three double bonds. Under the influence of the desaturase and elongase enzymes, omega-3 is converted to eicosapentaenoic acid, which is a fatty acid that is 20 carbons long and contains five double bonds. EPA is the precursor compound for the conversion to a group of chemicals called the series 3 prostaglandins (PGE3), which provide anti-inflammatory activity, (1) enhance the immune system, thin the blood, and lower blood pressure.

Dosage Info

Dosage Range

170mg to 3.6 grams of EPA daily, or 3 to 12 grams of fish oil concentrate daily.

Most Common Dosage

1-2 grams of EPA daily.

Dosage Forms

Capsules and tablets.

Adult RDI

None established

Adult ODA

None established

RDA

• : None established

Interactions and Depletions

Interactions

• orlistat
• chitosan
• Bile acid sequestrants
• mineral oil
• olestra
• Anticoagulant medications

Active Forms

Eicosapentaenoic acid

Absorption

EPA is absorbed from the intestinal tract, but since it is a fat, absorption is dependent on the amount of fat being consumed at that particular meal. One study reported that the absorption of EPA and DHA fish oils was increased three-fold when consumed with a high-fat meal. (2)

Toxicities & Precautions

General

Individuals who ingest supplemental EPA are advised to take additional antioxidants, especially vitamin E, to protect against free radical oxidation in the body. (3)

Side Effects

Some people who take supplemental EPA in the form of fish oil complain of gastrointestinal burping and belching, which causes a “fishy” odor.

Functions in the Body

Series 3 prostaglandins

EPA is the precursor to the series 3 prostaglandins (PGE3), which provide anti-inflammatory activity, enhance the immune system, and reduce platelet stickiness and blood pressure. (4)

Cellular membranes

Increased amounts of EPA in cellular membranes will help reduce the amount of pro-inflammatory omega-6 fat known as arachidonic acid in cellular membranes. (5)

Leukotriene B5

In leukocytes, through the lipoxygenase pathway, EPA metabolism produces leukotriene B₅, which provides anti-inflammatory activity and reduces platelet adhesion. (6)

Prostacyclin I3

In endothelial cells, through the cyclooxygenase pathway, EPA metabolism produces prostacyclin I₃, which relaxes blood vessels and reduces platelet aggregation. (7)

Lowering triglycerides

EPA plays a major role in lowering triglycerides in the body. (8) , (9)

Clinical Applications

Elevated Triglycerides

Studies indicate that EPA (not DHA) is the omega-3 fatty acid that is primarily responsible for lowering elevated levels in humans. (10)

Angina Pectoris

Studies indicate that a fish oil concentrate rich in EPA given to heart disease patients resulted in decreased platelet aggregation along with a significant reduction in angina attacks and the use of nitroglycerin medications. (11)

Cardiac Arrhythmias

Studies reportedly reveal that EPA is able to prevent and correct potentially fatal cardiac arrhythmias and stabilize the electrophysiology of the heart. (12)

Crohn’s Disease

Therapy with longer-chain omega-3 fatty acids, EPA and DHA, decrease the inflammatory activity in patients with Crohn’s disease. (13) , (14)

Rheumatoid Arthritis

Patients consuming fish oils (EPA and DHA) reportedly have a substantial reduction in pro-inflammatory eicosanoids prostaglandin E(2) and leukotriene B(4), and up to a 90 percent reduction in pro-inflammatory cytokines. (15) In another trial, patients had significant reductions in tender points and swollen joints with high dose consumption of fish oils (54 mg/kg EPA and 36 mg/kg DHA), providing better improvement than low dose consumption (27 mg/kg and 18 mg/kg). In this 24-week study, patients on low-dose fish oils obtained significant improvement in eight of 45 clinical measurements, while those on high-dose fish oils gained significant improvement in 21 of 45 categories. (16)

Lupus

Studies indicate that therapy with eicosapentaenoic acid, usually in combination with DHA, provides substantial benefit to patients with lupus. The results of one study reported that oral supplementation of EPA and DHA induced prolonged remission of systemic lupus erythematosus (SLE) in 10 consecutive patients without any side effects. (17)

Bipolar disorder

Evidence suggests that long-chain omega-3 fatty acids contained in fish oils (EPA and DHA) exhibit mood-stabilizing properties in patients with bipolar disorder, which is also known as manic depressive illness. EPA and DHA seem to inhibit neuronal signal transduction pathways in a manner similar to lithium carbonate and valproate, which are medications frequently used to treat this disorder. In a four-month, double-blind, placebo-controlled trial, patients treated with the omega-3 fish oils exhibited a significantly longer period of remission, plus they scored better than the placebo group on virtually every outcome measure that was studied. (18) Researchers found that levels of EPA were significantly lower in bipolar mood disorder patients than in the control group and that supplementation of antioxidants and essential fatty acids may improve the patients’ symptoms. (19)

Asthma

Children who have a higher consumption of oily fish in their diets, which provide EPA and DHA, have significantly reduced incidences of asthma. This is potentially due to the fatty acids reducing the production of pro-inflammatory leukotrienes. (20)

Cancer

In an animal model, the addition of DHA/EPA to the diet resulted in a 35 to 46% reduction in tumor growth. Also, in cell culture studies, DHA resulted in a 46% decrease in cancer cell growth. (21)

Cardiovascular Disease

A study assessed the effect of omega-3 fatty acids on systemic arterial compliance (SAC). SAC is a measure of arterial elasticity and may serve as a marker for cardiovascular disease and related events. In this placebo controlled, randomized, double-blind trial, 38 individuals with dyslipidemias were randomly assigned to one of three groups: 3 g eicosapentaenoic acid (EPA) per day (n = 12), 3 g docosahexaenoic acid (DHA) per day (n = 12), or placebo (n = 14). Arterial functions, lipids and fatty acids were all measured prior to and following the treatment interventions. Compared to placebo the omega-3 fatty acids significantly increased the SAC. EPA increased SAC 36% and DHA increased SAC 27%. In addition, the omega-3 fatty acids significantly lowered the total and VLDL triacylgylcerol levels. (22)

Diabetes

EPA in combination with DHA improves insulin sensitivity in non-insulin dependent diabetes. (23) One study revealed that the membrane phospholipids of people with both type 1 and type 2 diabetes have significantly reduced levels of EPA. (24) EPA given to type 2 diabetics reportedly resulted in an increased production of prostacyclin I3, suggesting that EPA may help prevent the complications associated with diabetes, such as microangiopathy and occlusive vascular disease, as well as lower triglycerides, blood viscosity, and decreased platelet reactivity. (25)

Hypertension

EPA, in combination with DHA, provides a moderate decrease in both diastolic and systolic blood pressure in individuals with moderate hypertension. (26)

Psoriasis

In a cross-over trial, patients eating oily fish for a six-week period, which resulted in a rise in plasma eicosapentaenoic acid, exhibited modest clinical improvements in psoriasis compared to patients eating white fish, which did not alter EPA levels. (27) Modest improvement was also observed in a one-year trial where patients received only EPA, with a corresponding reduction in inflammatory leukotriene B4 (LTB4) and an increase in the formation of anti-inflammatory leukotriene B5 (LTB5). (28)

Ulcerative Colitis

Studies report that providing therapeutic doses of fish oils (EPA and DHA) to patients with ulcerative colitis results in suppression of immune reactivity and concurrent reduction in disease activity. (29) , (30)

Schizophrenia

The results of two double-blind, placebo-controlled trials indicate that eicosapentaenoic acid (EPA) provided substantial therapeutic benefits for patients with schizophrenia when taken in conjunction with antipsychotic medications or as a sole therapy. The researchers concluded that EPA may represent a new treatment approach for schizophrenia. (31) Researchers found that patients with schizophrenia had significantly lower levels of EPA and that supplementation may be of benefit to the patients. (32)

Eczema

After 12 weeks, patients consuming 1.8 grams of EPA daily experienced reduced scaling, itching, and overall improved skin lesions compared to placebo controls. (33)

Symptoms and Causes of Deficiency

A deficiency of EPA has become increasingly common for the following reasons:

Reduced consumption of cold water fish, which is the primary dietary source of EPA. Low-fat diets reduce consumption of EPA and other important fatty acids. Omega-3 (alpha linolenic acid), the dietary precursor to EPA, is typically removed from food to extend product shelf life. In the last half century, there has been a significant increase in the use of processed oils from the omega-6 family such as corn, sunflower, and safflower oils, which compete with and suppress the body’s ability to convert omega-3 to EPA. Consumption of large quantities of trans fatty acids from foods containing partially hydrogenated fats and oils inhibits the enzyme delta-6-desaturase, which is responsible for the conversion of omega-3 to EPA and DHA and also omega-6 to its longer chain fatty acids. (34) The following nutrients are required for proper function of delta-6 desaturase enzyme activity, which converts omega-3 to EPA and DHA. They are niacin, pyridoxine, ascorbic acid, and zinc. Thus, a deficiency of any of these nutrients could impair the biosynthesis of EPA and DHA. (35)

Some of the major symptoms of a deficiency of EPA include the following: growth retardation in infants; weakness; impaired vision and learning ability; behavioral changes; dry skin; edema; increased inflammation; sticky platelets; elevated blood pressure; elevated triglycerides; altered metabolism; and weakened immune system.

Dietary Sources

The richest dietary sources of EPA are the oils from cold water fish such as salmon, mackerel, herring, sardines, and other marine animals.

References

1. View Abstract: Read JA, Clarke SJ, Volker D. Nutritional and anti-inflammatory strategies in the treatment of advanced colorectal cancer – a pilot study. Asia Pac J Clin Nutr. 2004;13(Suppl):S93.
2. View Abstract: Lawson LD, et al. Absorption of eicosapentaenoic acid and docosahexaenoic acid from fish oil triacylglycerols or fish oil ethyl esters co-ingested with a high-fat meal. Biochem Biophys Res Commun. Oct1988;156(2):960-3.
3. View Abstract: Moison RM, et al. Dietary eicosapentaenoic acid prevents systemic immunosuppression in mice induced by UVB radiation. Radiat Res. Jul2001;156(1):36-44.
4. View Abstract: Calder PC. Immunoregulatory and anti-inflammatory effects of n-3 polyunsaturated fatty acids. Braz J Med Biol Res. Apr1998;31(4):467-90.
5. View Abstract: Heller A, Koch T, Schmeck J, van Ackern K. Lipid mediators in inflammatory disorders. Drugs. Apr1998;55(4):487-96.
6. View Abstract: Ikehata A, et al. Effect of intravenously infused eicosapentaenoic acid on the leukotriene generation in patients with active Crohn’s disease. Am J Clin Nutr. Nov1992;56(5):938-42.
7. View Abstract: Kinsella JE, Lokesh B, Stone RA. Dietary n-3 polyunsaturated fatty acids and amelioration of cardiovascular disease: possible mechanisms. Am J Clin Nutr. Jul1990;52(1):1-28.
8. View Abstract: Rambjor GS, et al. Eicosapentaenoic acid is primarily responsible for hypotriglyceridemic effect of fish oil in humans. Lipids. Mar1996;31 Suppl:S45-9.
9. View Abstract: Lovegrove JA, Lovegrove SS, Lesauvage SV, et al. Moderate fish-oil supplementation reverses low-platelet, long-chain n-3 polyunsaturated fatty acid status and reduces plasma triacylglycerol concentrations in British Indo-Asians. Am J Clin Nutr. Jun2004;79(6):974-82.
10. View Abstract: Rambjor GS, et al. Eicosapentaenoic acid is primarily responsible for hypotriglyceridemic effect of fish oil in humans. Lipids. Mar1996;31 Suppl:S45-9.
11. View Abstract: Saynor R, et al. The long-term effect of dietary supplementation with fish lipid concentrate on serum lipids, bleeding time, platelets and angina. Atherosclerosis. Jan1984;50(1):3-10.
12. View Abstract: Kang JX, Leaf A. Prevention of fatal cardiac arrhythmias by polyunsaturated fatty acids. Am J Clin Nutr. Jan2000;71(1 Suppl):202S-7S.
13. View Abstract: Ikehata A, et al. Effect of intravenously infused eicosapentaenoic acid on the leukotriene generation in patients with active Crohn’s disease. Am J Clin Nutr. Nov1992;56(5):938-42.
14. View Abstract: Belluzzi A, et al. Effects of new fish oil derivative on fatty acid phospholipid-membrane pattern in a group of Crohn’s disease patients. Dig Dis Sci. Dec1994;39(12):2589-94.
15. View Abstract: James MJ, et al. Dietary polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr. Jan2000;71(1 Suppl):343S-8S.
16. View Abstract: Kremer JM, et al. Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Clinical and immunologic effects. Arthritis Rheum. Jun1990;33(6):810-20.
17. View Abstract: Das UN. Beneficial effect of eicosapentaenoic and docosahexaenoic acids in the management of systemic lupus erythematosus and its relationship to the cytokine network. Prostaglandins Leukot Essent Fatty Acids. Sep1994;51(3):207-13.
18. View Abstract: Stoll AL, et al. Omega 3 fatty acids in bipolar disorder; A preliminary double-blind, placebo-controlled trial. Archives of General Psychiatry. May1999;66:407-412.
19. View Abstract: Ranjekar PK, Hinge A, Hegde MV, et al. Decreased antioxidant enzymes and membrane essential polyunsaturated fatty acids in schizophrenic and bipolar mood disorder patients. Psychiatry Res. Dec2003;121(2):109-22.
20. View Abstract: Hodge L, et al. Consumption of Oily Fish and Childhood Asthma Risk. MJA. Feb1996;164:137-140.
21. View Abstract: Colquhoun A, Ramos KL, Schumacher RI. Eicosapentaenoic acid and docosahexaenoic acid effects on tumour mitochondrial metabolism, acyl CoA metabolism and cell proliferation. Cell Biochem Funct. Jun2001;19(2):97-105.
22. View Abstract: Nestel P, Shige H, Pomeroy S, Cehun M, Abbey M, Raederstorff D. The n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid increase systemic arterial compliance in humans. American Journal of Clinical Nutrition. Aug2002;76(2):326-330.
23. View Abstract: Popp-Snijders C, et al. Dietary supplementation of omega-3 polyunsaturated fatty acids improves insulin sensitivity in non-insulin-dependent diabetes. Diabetes Res. Mar1987;4(3):141-7.
24. View Abstract: Horrobin D. Essential Fatty Acids in the Management of Impaired Nerve Function in Diabetes. Diabetes. 1997;46(Suppl. 2):S90-S93.
25. View Abstract: Nishikawa M, et al. Effects of eicosapentaenoic acid (EPA) on prostacyclin production in diabetics: Gc/MS analysis of PGI2 and PGI3 levels. Meth. Find. Exp. Clin. Pharmnacol. 1997;19(6):429-433.
26. View Abstract: Prisco D, et al. Effect of medium-term supplementation with a moderate dose of n-3 polyunsaturated fatty acids on blood pressure in mild hypertensive patients. Thromb Res. Aug1998;91(3):105-12.
27. View Abstract: Collier PM, et al. Effect of regular consumption of oily fish compared with white fish on chronic plaque psoriasis. Eur J Clin Nutr. Apr1993;47(4):251-4.
28. View Abstract: Kojima T, et al. Long-term administration of highly purified eicosapentaenoic acid provides improvement of psoriasis. Dermatologica. 1991;182(4):225-30.
29. View Abstract: Almallah YZ, et al. Distal proctocolitis and n-3 polyunsaturated fatty acids (n-3 PUFAs): the mucosal effect in situ. J Clin Immunol. Jan2000;20(1):68-76.
30. View Abstract: Grimminger F, et al. Influence of intravenous n-3 lipid supplementation on fatty acid profiles and lipid mediator generation in a patient with severe ulcerative colitis. Eur J Clin Invest. Nov1993;23(11):706-15.
31. View Abstract: Peet M, Laugharne JD, Mellor J, Ramchand CN. Essential fatty acid deficiency in erythrocyte membranes from chronic schizophrenic patients, and the clinical effects of dietary supplementation. Prostaglandins Leukot Essent Fatty Acids. Aug1996;55(1-2):71-5.
32. View Abstract: Ranjekar PK, Hinge A, Hegde MV, et al. Decreased antioxidant enzymes and membrane essential polyunsaturated fatty acids in schizophrenic and bipolar mood disorder patients. Psychiatry Res. Dec2003;121(2):109-22.
33. View Abstract: Bjorneboe A, et al. Effect of dietary supplementation with eicosapentaenoic acid in the treatment of atopic dermatitis. Br J Dermatol. 1987;117(4):463-69.
34. View Abstract: Booyens J, et al. The role of unnatural dietary trans and cis unsaturated fatty acids in the epidemiology of coronary artery disease. Med Hypotheses. Mar1988;25(3):175-82.
35. View Abstract: Horrobin DF. Loss of delta-6-desaturase activity as a key factor in aging. Med Hypotheses. Sep1981;7(9):1211-20.