ARTICLE
Auteur(s) : Francesco VISIOLI1, Patrizia
RISE1, Franca MARANGONI1, Claudio
GALLI2
1 University of Milan, Department of
Pharmacological Sciences
2 Department of Pharmacological Sciences, Via
Balzaretti 9, 20133 Milan, Italy
Tel: + 39.0250318309
Fax: + 39.0250318284
<claudio.galli@unimi.it>
Several minor components in the diet cannot be synthesized “de
novo” in the body but, at the same time, play essential roles in
vital processes. These compounds are defined as “nutritionally
essential”. Several other types of compounds ingested with the diet
are able to modulate biological processes and functions and,
therefore, they are endowed with “pharmacological” or, eventually,
“toxicological” properties or features.
Food generally consists of animal and plant tissues and organs
and, therefore, it provides complete cellular machineries (e.g.
enzymes, cofactors, structural components, etc.) rather than pure
chemicals. A remarkable exception to this situation is represented
by milk, the only type of food in which an array of complex
molecules – with primary nutritional roles – is
arranged in highly organized micellar dispersions. This represents
a very efficient strategy specifically developed by nature to
optimize the delivery of nutrients to rapidly growing and
nutritionally demanding organisms, such as those of infants.
The essentiality of the different nutrients and the observation
that they may be beneficial for our health have promoted their
utilization as “drugs” (or bioactive compounds), frequently without
paying attention to optimize the formulation for their delivery. In
fact, it is frequent that, in clinical studies, such preparations
proved to be less effective than what was predictable from
epidemiological data based on the intakes through the diet, e.g. in
the case of certain antioxidants.
This may apply, to some extent, to several lipid-soluble nutrients
which are quantitatively minor components of the diet, such as
lipid-soluble antioxidants and minor fatty acids (FA). These
compounds are generally ingested together with the bulk of fats,
being part of natural foods or food items (oils and fats) derived
from them. The independent ingestion of small amounts of lipid
soluble compounds dissociated from their natural matrix and often
not with regular meals may result in less efficient
bioavailability.
In particular, the Western diet provides an average of less than
100 mg/day of the long chain (LC) omega 3 fatty acids EPA
(eicosapentaenoic acid, 20:5n-3) and DHA (docosahexaenoic acid,
22:6n-3) – mainly found in fish – out of a
total fat intake of about 100 g/day. These minor components
have been shown to be protective with respect to various
atherogenic factors, on the bases of well documented
epidemiological and clinical studies [1, 2].
Various studies have indeed shown that populations consuming
fish two-three times/week, i.e. ingesting relatively small amounts
of omega 3 FA, are protected when compared with abstainers,
although fish intake may provide other protective agents in
addition to omega 3 FA. In addition, controlled studies [3]
have shown that the intake of fish rich in omega 3 is
protective toward cardiovascular events, and that fish is more
protective than pharmaceutical preparations providing equivalent
amounts of omega 3 fatty acids [4]. The different
bioavailability of omega 3 fatty acids taken in food or as
capsules, however, has never been explored in details.
Study design
This chapter describes the results of studies that have been
previously reported [5], focussing more specifically on the
practical implications of the results. We have investigated, in
healthy subjects, the relationships between the consumption of
either salmon, with given amounts of EPA and DHA, and the
administration of EPA and DHA ethyl esters, by measuring their
levels in plasma lipids. We also include the results of a previous
study with different preparations of EPA and DHA, administered to
similar groups of healthy individuals with an identical study
design [6]. All treatments were carried out for a period of six
weeks. Eight healthy subjects (four males and four females, aged
26-38 y) consumed 100 g/d of smoked salmon, which
provided 383 mg of EPA and 544 mg of DHA. The amounts of
EPA and DHA in the smoked salmon were measured through a
quantitative analytical procedure. Two groups of eight subjects
each (six males and two females) took one or three capsules of fish
oil/day (Now Foods, Bloomingdale, IL), providing 150 mg EPA
and 106 mg DHA or 450 mg EPA and 318 mg DHA as ethyl
esters, respectively.
Participants did not eat fish during the three weeks preceding the
study. Blood was drawn at – 2, 0, 3, and 6 weeks
(T–2, T0, T3, T6) of
treatment in the morning in fasting conditions, using
Li+ heparin as the anticoagulant, and plasma was
immediately prepared. Complete lipid analysis was carried out at
each time point. Fatty acid data were expressed as percentages of
total fatty acids, as µg/mg total lipids, and as µg/ml plasma for
each fatty acid. In the previous study [5], carried out with the
same protocol, three (1 290 mg EPA and 960 mg DHA)
or six (2 580 mg EPA and 1920 mg DHA) one-g capsules of a
different type of preparation/day were given to two groups of eight
healthy subjects. Measurements of fatty acid concentrations (µg/mg
TL) allow to evaluate the absolute changes following treatments.
There was no appreciable change in EPA and DHA levels between
T–2 and T0, and we are therefore reporting
only the plasma increments between T0 and T6
for all four treatments: one capsule/day and fish, in this study,
and three and six capsules/day in the previous study. Increments
(µg/mg plasma total lipids) of both EPA and DHA are well correlated
with the doses in the studies with capsules, with linear
relationships that were expressed by equations with R2
very close to 1.0. On the other side, it was not possible to define
any kind of equation which would include also the data obtained
with fish. The excellent relationships for increments vs
doses are rather surprising considering that studies were carried
out several years apart, although with an identical protocol (table 1). It is also quite apparent that
increments with the dose are much smaller for DHA than for EPA
(slopes 0.002 vs 8.67, respectively). The most striking
findings are that the increments of EPA and especially of DHA after
fish intake are markedly much higher than with capsules. In fact,
for EPA an increment of 8.8 µg/mg TL was obtained with an
intake of 383 mg/day through fish ingestion vs an
increment of 6.3 µg/mg TL (i.e. about 30% lower) after the
intake of 450 mg/day (i.e. 17% higher) with a capsule. The
difference between fish vs capsules is even greater in the
case of DHA. With a daily dose of 544 mg DHA from fish, plasma
increments were almost double than those obtained with
1 920 mg with capsules, that is a 3.5 fold higher
dose. In order to obtain the same increments with a pharmaceutical
preparation, assuming that linearity between intakes and plasma
increments is retained, it would require 3 920 mg,
corresponding to 12 capsules (320 mg DHA/capsule).
Table 1. Net increments of
plasma eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids after
supplementation of healthy volunteers with either fish or fish oil
capsules (cps).
|
EPA |
DHA |
|
Net increment µg/mg
total lipids |
| Fish (383 mg EPA + 544 mg
DHA) |
8.8 ± 1.2 |
8.5 ± 2.6 |
| 1 cps (150 mg
EPA + 106 mg DHA) |
2.8 ± 0.3 |
2.1 ± 0.7 |
| 3 cps (450 mg
EPA + 318 mg DHA) |
6.3 ± 1.3 |
3.2 ± 1.3 |
| 3 cps (1 290 mg
EPA + 960 mg DHA) |
13.2 ± 2.5 |
3.3 ± 1.3 |
| 6 cps (2 580 mg
EPA + 1 920 mg DHA) |
26.4 ± 3.3 |
4.8 ± 1.9 |
Data are means ± SD. For protocol details, including
doses, please refer to the original papers.
Equations for the increments related to capsules intakes:
EPA,
y = 1.06 + 9.78 × 10 – 3
R2 = 1.00
DHA,
y = 2.19 + 1.34 × 10 – 3
R2 = 0.929
Discussion
The data obtained by comparing the increments in EPA and DHA
levels in plasma lipids of a various groups of healthy subjects
after administration as pharmaceutical preparations vs fish
provide convincing evidence that the form of administration of
small amounts of omega 3 fatty acids and, possibly, also their
chemical features (triglyceride vs ethyl esters) affects the
bioavailability of these compounds. The data were calculated as
absolute increments in the amounts, as the conventional way of
expressing fatty acid data, i.e. percentages, does not provide a
correct overview of the FA status. In fac, by expressing the whole
FA profile in terms of percentages, i.e. added up to a total of
100, one implies that increments of certain compounds are
counterbalanced by compensatory reduction(s) of other FAs.
Measurement of absolute amounts (µg/mg total lipids or /mL) and of
their changes after administration provides quantitative
information on relationship between intakes and levels in the
circulation, i.e. on the bioavailability. The results therefore
were expressed as changes in circulating levels in relation to
intakes (amounts/day).
Greater bioavailability of omega 3 fatty acids from fish than
from pharmaceutical preparations is predictable as it is associated
with a large mass of fats and thus administered in a very diluted
form. Further, this route of intake is associated with a mass of
tissue and fats that activate digestive processes, including those
involved in lipid digestion and absorption. In addition, the
mucosal surface involved in the absorption of a large mass is
certainly greater than that involved in the absorption of a small
volume.
Capsules, conversely, provide just a small lipid bolus and, in the
absence of a concomitant intake of other fats, the processes for
lipid absorption may not be adequately activated. The results,
quite beyond our prediction, may provide some clue as to why fish
may be better than capsules in term of providing omega 3 fatty
acids. Also, the observations that fish consumption, even at
relatively low doses and few times/week, is highly protective
toward cardiovascular diseases may find some grounds in our data.
n
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