Omega-3 Research

Eicosapentaenoic Acid (EPA)

DESCRIPTION

Eicosapentaenoic acid, or EPA, is a major component of fish oil. It is a long-chain polyunsaturated fatty acid of the n-3 or omega-3 type. EPA is an all cis polyunsaturated fatty acid containing 20 carbons and 5 double bonds. EPA is also known as EPA; C20: 5n-3 and cis-5, 8, 11, 14,17-eicosapentaenoic acid. The structural formula is as follows:

EPA is a precursor of the series-3 prostaglandins, the series-5 leukotrienes and the series-3 thromboxanes, which are anti-artherogenic and antithrombogenic. EPA is found naturally in the form of triacylglycerols (TAGs).

ACTIONS AND PHARMACOLOGY

ACTIONS

Supplemental EPA may have anti-inflammatory, antithrombotic and immunomodulatory activities. It may also have triglyceride-lowering activity.

MECHANISM OF ACTION

The possible anti-inflammatory, antithrombotic and immunomodulatory actions of supplemental EPA are probably due mostly to EPA's role in eicosanoid physiology and biochemistry. Eicosanoids are produced by the metabolism of the n-3 or omega-3 polyunsaturated fatty acids, and in particular the 20 carbon n-3 polyunsaturated fatty acid, arachidonic acid. These eicosanoids are of the leukotriene 4 series and thromboxane 2 series. Leukotriene B4 (LTB4) and thromboxane A2 (TXA2) stimulate leukocyte chemotaxis, platelet aggregation and vasoconstriction. These eicosanoids are thrombogenic and artherogenic.

On the other hand, EPA is metabolized to leukotriene B5 (LTB5) and thromboxane A3 (TXA3), eicosanoids that promote vasodilation, inhibit platelet aggregation and leukocyte chemotaxis and are anti-artherogenic and anti-thrombotic.

The triglyceride-lowering effect of EPA results from inhibition of lipogenesis and stimulation of fatty acid oxidation. Fatty acid oxidation of EPA occurs mainly in the mitochondria. (For further discussion on the action of EPA, see the Fish Oil monograph.)

PHARMACOKINETICS

See the Fish Oil monograph.

INDICATIONS AND USAGE

EPA may be indicated for lowering elevated triglycerides in those who are hyperglyceridemic. EPA may play some therapeutic role in those with cystic fibrosis to reduce disease severity and may similarly play a role in type 2 diabetics in retarding the progression of diabetic nephropathy. However, the latter two indications require clinical trials and documentation to establish this.

See the monograph on Fish Oils for further information.

RESEARCH SUMMARY

A double-blind, placebo-controlled study was performed to determine the triglyceride-lowering effect of EPA and DHA by themselves. In the seven-week study, 234 healthy men were randomly given the following: EPA in the ethyl ester at a dose of 3.8 grams daily, the ethyl ester of DHA at

3.6 grams daily or corn oil at 4 grams daily as a placebo. Triglycerides decreased by 21% in the EPA group and by 26% in the DHA group when compared with placebo. Some retroconversion of DHA to EPA was found, but no significant conversion of EPA to DHA was observed. A small, but significant increase in HDL-cholesterol was seen in the DHA group, and a small, but significant, decrease of total cholesterol and apolipoprotein A1 (Apo A1) was noted in the EPA group. A randomized, double-blind, placebo-controlled crossover trial comparing fish oil supplementation against placebo was performed to determine fish oil effects on markers of clinical state, neutrophil function and lung inflammation in 16 patients with cystic fibrosis who were colonized with Pseudomonas aeruginosa. The fish oil used in this trial contained 2.7 grams of EPA (the amount of DHA in the capsules was not mentioned), which the subjects received daily for a six-week period. The placebo group received olive oil. The fish oil-supplemented group showed a significant reduction in disease severity and sputum volume and in the pathogenesis of lung damage.

The study also showed that EPA-rich fish oil dampens the damaging effects of the circulating neutrophils in the chronic inflammatory process. There is a reduction of leukotriene B4, which is believed to play an important role in the pathogenesis of lung damage in cystic fibrosis. The effect of EPA on the progression of diabetic nephropathy has been studied in rats and humans. Measurement of urinary albumin is a key marker in determining renal function in diabetics. In a six-month study with Wister rats made diabetic by administration of streptozotocin, the ethyl ester of EPA was given to 16 rats, while an equal number served as the control. The mean microalbuminuria of the EPA group was significantly lower than that of the control group after four months, and this significant difference persisted for the remaining two months of the trial.

In a human study with type 2 diabetics, administration of 900 milligrams daily of the ethyl ester of EPA resulted in a significant decrease in urinary albumin excretion at three months after start of treatment; this reduction was sustained for a year after the start of treatment. These studies suggest that EPA supplementation of diabetics with albuminuria might retard the progression of diabetic nephropathy.

See the monograph on Fish Oil for further discussion.

CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS.

CONTRAINDICATIONS

None known.

PRECAUTIONS

Because of possible antithrombotic activity of EPA, it should be used with caution in those who take warfarin (Coumadin) and by those with hemophilia. Similarly, EPA should be stopped before surgical procedures.

EPA supplements should be used by children, pregnant women and nursing mothers only if recommended and monitored by a physician.

ADVERSE REACTIONS

There have been no reports of serious adverse events in those taking EPA supplements, even up to 15 grams daily, for prolonged periods of time. Those side effects that have been reported include mild gastrointestinal upsets such as nausea and diarrhea, halitosis, eructation, "fishy" smelling breath, skin and even urine. The blood-thinning effects can cause occasional nosebleeds and easy bruising.

INTERACTIONS

Interactions may occur between EPA supplements and aspirin and other non-steroidal antiinflammatory drugs and herbs such as garlic (Allium sativum) and ginkgo (Ginkgo biloba). Such interactions might be manifested by increased susceptibility to bruising, nosebleeds, hemoptysis, hematemesis, hematuria and blood in the stool. Most who take EPA supplements and the above drugs or herbs do not suffer from these problems and if they occur, they are rare. If they do occur, the EPA dose should be lowered or discontinued.

Conflicting results have been reported regarding the effects of EPA supplements on glycemic control in non-diabetics with glucose intolerance, and those with type 2 diabetes. Some early studies indicated that EPA supplements might have detrimental effects in those groups. Recent, better designed studies have not reported these adverse effects. There is no evidence that EPA supplements have detrimental effects on glucose tolerance, insulin secretion or insulin resistance in non-diabetic subjects. Diabetics should discuss the use of these supplements with their physicians and note if the supplements affect their glycemic control. Diabetics who take EPA supplements should be monitored by their physicians.

OVERDOSAGE

None known.

DOSAGE AND ADMINISTRATION

EPA is typically available in fish oil in combination with DHA. The usual ratio of EPA to DHA in these preparations is about 1.5. Fish oil preparations are available with higher ratios up to about

3. There is an ethyl ester form of EPA.

See Fish Oil monograph for further discussion.

LITERATURE

Fujikawa M, Yamazaki K, Hamazaki T, et al. Effect of eicosapentaenoic acid ethyl ester on albuminuria in streptozotocin-induced diabetic rats. J Nutr Sci Vitaminol. 1994; 40: 49-61. Grimsgaard S, Bønaa KH, Hansen JB, Nordøy A. Highly purified eicosapentaenoic acid and docosahexaenoic acid in humans have similar triacylglycerol-lowering effects but divergent effects on serum fatty acids. Am J Clin Nutr. 1997; 66:649-659.

Lawrence R, Sorrell T. Eicosapentaenoic acid in cystic fibrosis: evidence of a pathogenic role for leukotriene B4. Lancet. 1993; 342:465-469.

Madsen L, Rustan QC, Vaagenes H, et al. Eicosapentaenoic and docosahexaenoic acid affect mitochondrial and peroxisomal fatty acid oxidation in relation to substrate preference. Lipids. 1999; 34:951-963.

Shimizu H, Ohtani K, Tanaka Y, et al. Long-term effect of eicosapentaenoic acid ethyl (EPA-E) on albuminuria of non-insulin dependent diabetic patients. Diabetes Res Clin Pract. 1995; 28:35-40. Terano T, Hira A, Hamazaki T, et al. Effect of oral administration of highly purified eicosapentaenoic acid on platelet function, blood viscosity and red blood cell deformability in healthy human subjects. Atheroscler. 1983; 46: 321-331.

See Fish Oil monograph for further literature.