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Vol.18, No. 8August 1996
Potential AdverseEffects of Long-TermConsumption of (n-3)Fatty Acids
*
Oregon State University 
 Jean A. Hall, DVM, PhD
T
he potential benefits of dietary supplementation with (n-3) (also called
ω
-3) fatty acids have aroused great interest. As a result, various petfoods and fatty acid supplements rich in (n-3) fatty acids are currently marketed for administration to dogs and cats. However, long-term studies of the effects of dietary supplementation with (n-3) fatty acids in these species arelacking. Potential toxic or adverse effects of long-term (n-3) fatty acid con-sumption should not be ignored but should be investigated in conjunction with ongoing research to determine whether diseased dogs or cats will benefitfrom the use of these agents.
POLYUNSATURATED FATTY ACIDSOverview
Fatty acids are classified as saturated, monounsaturated, or polyunsaturatedon the basis of the number of double bonds in the fatty acid’s carbon chain.Each class of fatty acids has different properties and unique biologic character-istics.
1,2
Polyunsaturated fatty acids are named according to the position of the firstdouble bond—counting from the methyl end of the molecule (Figure 1). Thetwo most important series of polyunsaturated fatty acids are the (n-3) series(which have the first double bond located at the third carbon atom) and the
Continuing Education Article
V
FOCAL POINTKEY FACTS
s
The risk of bleeding afterprolonged intake of (n-3) fattyacids seems to be very low.
s
A high intake of (n-3) fatty acidscould lead to impairment oflinoleic-acid metabolism and adeficit of its fatty-acid derivatives,which may not be risk free.
s
A possible adverse effect of highlevels of dietary (n-3)fatty acidsis that their accumulation intissue makes the tissuevulnerable to lipid peroxidation.
s
Whether the observed decreasesin immune and inflammatoryresponses are sufficient tocompromise normal hostdefenses is unknown.
5
The long-term effects of (n-3)fatty acid supplementation forcompanion animals have notbeen investigated.
*
Editor’s Note: 
This article, which was derived in part from a presentation at the Thir-teenth ACVIM Veterinary Medical Forum, is presented to give the reader an overview of potential adverse effects of (n-3) fatty acid supplementation. Although these productsappear to be very safe as currently used, their long-term effects in companion animalshave not been studied. Most of the information regarding adverse effects is taken fromstudies of humans. A second article describing the benefits of fatty acid supplementationin small animals will be presented in an upcoming issue of 
Compendium.
 As with allnew therapies, practitioners must weigh the costs and benefits before making recom-mendations.
 
(n-6) series (which have thefirst double bond located atthe sixth carbon atom).Both linoleic acid and
α
-linolenic acid, which arethe precursors of the (n-6)and (n-3) series, respective-ly, are essential fatty acidsbecause mammals cannotsynthesize them from otherseries of fatty acids. Mam-mals lack the enzymes tointroduce double bonds atcarbon atoms before theninth carbon atom in thefatty acid chain (countingfrom the methyl end).Therefore, these essentialfatty acids must be suppliedin the diet. Subsequent de-saturation and elongationproceed only toward thecarboxyl terminus of the fatty acid.In general, fatty acids from both series can be elon-gated and desaturated. Cats, however, have reduced
6desaturase and therefore cannot adequately convertlinoleic acid to arachidonic acid. Thus, arachidonicacid and linoleic acid must be supplied by the cat
sdiet.
3
The elongation (increase in the number of carbonatoms) and desaturation (increase in the number of double bonds) of linoleic acid and
α
-linolenic acid arecatalyzed by the same enzymes (Figure 2). However, in-terconversion between (n-3) fatty acids and (n-6) fatty acids is impossible because elongation and desaturationoccur only toward the carboxyl terminus of the fatty acid. Arachidonic acid (which is derived from the [n-6]fatty acid linoleic acid) and eicosapentaenoic acid(which is derived from the [n-3] fatty acid
α
-linolenicacid) are both fundamental components of cytoplasmicmembranes. Further metabolism of these fatty acidsleads to the generation of eicosanoids (Figure 3).Prostaglandins, thromboxanes, and leukotrienes are allderived from the metabolism of (n-3) and (n-6) fatty acids through reactions involving cyclooxygenase andlipoxygenase enzymes.Eicosanoids are important mediators of cellular reac-tions. The eicosanoids derived from arachidonic acidand eicosapentaenoic acid have different biologic ef-fects. For example, the eicosanoids that are derivedfrom eicosapentaenoic acid are in general much less po-tent inducers of inflammation than are the eicosanoidsderived from arachidonicacid. Although no conversionbetween (n-3) and (n-6) se-ries of fatty acids takesplace, inhibition and com-petition between fatty acidsof different series have beendemonstrated.
4
6
For exam-ple, the metabolism of 
α
-linolenic acid is inhibitedby members of the linoleic-acid family: arachidonicacid,
γ 
-linolenic acid, andlinoleic acid. The competi-tive equilibrium betweenlinoleate and linolenate canbe displaced in either direc-tion, and the fatty acid fa-vored in the competitiondepends on the relative lev-els of those fatty acids inthe diet.
6
 An excess of (n-6) fatty acids reduces themetabolism of 
α
-linolenic acid, thus possibly leading toa deficit of its metabolites, including eicosapentaenoicacid. However, the (n-3) fatty acids are much more ef-fective in inhibiting (n-6) fatty acid metabolism thanvice versa.
4
Sources
Various diets and nutritional supplements are cur-rently marketed as sources of (n-3) fatty acids for com-panion animals. The fatty acid ratios of commercialdog foods vary widely, depending on the source of fat.Diets containing safflower oil or corn oil are likely to behigh in (n-6) fatty acids and to have a ratio of (n-6) to(n-3) greater than 30:1. Also, various (n-3) fatty acidsupplements for human use are available over thecounter.
(N-3) FATTY ACID SUPPLEMENTATIONPotential Clinical Benefits
Dietary supplementation with (n-3) fatty acids may produce desirable clinical effects in dogs or cats withvarious diseases.
2,7
9
In addition, extrapolation fromstudies of animal models and human trials indicatesthat these fatty acids have the potential to yield variousclinical benefits (see the box). Some of the potentialbenefits for cancer patients relate to the ability of (n-3)fatty acids to decrease production of certain cytokinesthat mediate cancer cachexia.Because of their ability to modify eicosanoid produc-tion, (n-3) fatty acids have the potential to alter func-
Small Animal
The Compendium 
August 1996
ARACHIDONIC ACID
s
EICOSAPENTAENOIC ACID
s
FATTY ACID RATIOS
Linoleic acid 18:2 (n-6)COOHCOOHCH
3
CH
3
α
-Linolenic acid 18:3 (n-3)
Figure 1—
Polyunsaturated fatty acids of the (n-6) series(linoleic acid 18:2 [n-6]) and of the (n-3) series (
α
-linolenicacid 18:3 [n-3]). The number of carbon atoms is listed be-fore the colon and the number of double bonds after thecolon.
 
tion or disease processes in many different body sys-tems (e.g., the gastrointestinal and renal systems) thatare influenced by prostaglandins.
13
17
 Whether dietary supplementation with (n-3) fatty acids will be benefi-cial in the treatment of the disease processes discussedremains to be seen.
Potential Adverse Effects
Many of the studies cited below have been conducted with research animals or with human patients. Thedosages used, the duration of the feeding trials, andthus the biologic responses often vary between studies.For example, the response to fish consumption may becompared with the responseto fish-oil consumption orto a specific dose of (n-3)fatty acids. In addition,there are inherent problemsin extrapolating from otherspecies to dogs and cats.The effects of dietary supplementation with (n-3)fatty acids for dogs and catshave not been well studied.Experimental data on thecorrect dosage of (n-3) fatty acids or the best ratio of (n-6) to (n-3) fatty acids in thediet for maximizing benefitsand minimizing side effectsare few. Nevertheless, the fol-lowing safety issues shouldbe considered before long-term dietary supplementa-tion with (n-3) fatty acids isrecommended.
Contamination of Sources 
Fish oil, which is a majordietary source of (n-3) fatty acids, may contain heavy metals and organic chemi-cals that were concentratedin the lipids of fish caughtin waters contaminated withindustrial by-products (e.g.,dioxin and dibenzofurans).
18
These findings do not war-rant restriction of the con-sumption of fish oil butshould serve as a reminderof potential food contami-nation by these toxic substances. Heavy metals and pes-ticides may be removed during the processing of fish-oil concentrates.
19
Veterinarians prescribing (n-3) fatty acid supplements should ask commercial suppliers if the products are free of contaminants. Most manufac-turers carefully screen their oils to ensure that they donot contain unwanted substances.
Hemostatic Abnormalities 
Many studies have addressed the concern about anincreased risk of bleeding after prolonged intake of (n-3) fatty acids,
20
but the risk seems to be very low.
21
Pro-thrombin time, activated partial thromboplastin time,
The Compendium 
August 1996Small Animal
DIOXIN
s
DIBENZOFURANS
s
HEAVY METALS
s
PESTICIDES
Figure 2
Fatty acid biosynthesis: the elongation and desaturation of the (n-6) fatty acidlinoleic acid and the (n-3) fatty acid
α
-linolenic acid.
Linoleic acid18:2 (n-6)
γ 
-Linolenic acid18:3 (n-6)Dihomo-
γ 
-linolenic acid20:3 (n-6)Arachidonic acid20:4 (n-6)22:4 (n-6)22:5 (n-6)
α
-Linolenic acid18:3 (n-3)Stearidonic acid18:4 (n-3)Eicosatetraenoic acid20:4 (n-3)Eicosapentaenoic acid20:5 (n-3)22:5 (n-3)Docosahexaenoic acid22:6 (n-3)
(n-6) Series(n-3) Series
6 Desaturase(desaturation)Elongase(elongation)
5 Desaturase(desaturation)Elongase(elongation)
4 Desaturase(desaturation)
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