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Adesina A Jonathan / JPBMS, 2012, 20 (08)
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ISSN NO- 2230 – 7885
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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
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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
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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
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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
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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. Polyunsaturated fatty acids can selectively kill the
tumor cells and can actually behave as anti-angiogenic
substance. The physiological efficacy of the native oils
likewise cannot simply be related to their content of EFAs.
The precise triglyceride structure of the oil, rather than
simply amount of EFAs it contains, may be of major
importance [3,78,82].
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Conflict of Interest:-None
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Corresponding Author:ADESINA ADEOLU JONATHAN
Department of Chemistry. Ekiti State University,
PMB 5363, Ado Ekiti. Nigeria.
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