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A
compartmental model (J Lipid Res 2001
Aug;42(8):1257-1265) was used to assign rate constants for d5-18:3n-3,
d5-20:5n-3, d5-22:5n-3, and d5-22:6n-3 in the
plasma of ten human subjects eating diets with different long-chain PUFA
content. Subjects ate their normal
self-selected diets for three weeks, then a beef-based diet for three weeks and
then a fish-based diet for three more weeks.
At the beginning of the third, sixth and ninth week, subjects consumed
one gram of d5-18:3n-3 ethyl ester.
With all diets, less than 1% of the plasma 18:3n-3 was utilized for
synthesis of long-chain PUFA. While subjects were consuming the fish-based diet
there was a 70% reduction in the value of the coefficient for transfer of the
isotope from the 22:5n-3 compartment to 22:6n-3 compared to the prior
beef-based diet. In conjunction with
this, the "turnover" rate of plasma d5-22:6n-3 was also
reduced. The primary effect of a
fish-based diet relative to a beef-based diet on the kinetics of n-3 metabolism
was inhibiting synthesis of 22:6n-3 from 22:5n-3, perhaps by feed-back control
mechanisms responsive to the plasma concentration of 22:6n-3. RJ. Pawlosky, JR. Hibbeln, Y.
Lin and N. Salem Jr. Effects of beef- and fish-based diets on the kinetics of
n-3 fatty acid metabolism in human subjects.
Am. J. Clin. Nutr. 77: 565-72; 2003.
Gender influenced the coefficient for
conversion of 22:5n-3 to 22:6n-3, with a much greater value (p = 0.001) in
women (k = 0.041 +/- 0.007) than men (k = 0.012 +/- 0.004). The nearly 3-fold greater use of 22:5n-3 for
22:6n-3 synthesis during the beef-based diet (Figure 1) did not reach
statistical significance (p = 0.08) during the ad-lib diet. Men and women eating the fish-based diet
showed about equal utilization of 22:5n-3 for 22:6n-3 synthesis (Figure
1). The regulation of n-3 fatty acid metabolism
in women seems more sensitive to dietary alterations, possibly due to hormonal
factors. RJ. Pawlosky, JR. Hibbeln,
Y. Lin and N. Salem Jr. Effects of gender on n-3 fatty acid metabolism in
humans. Brit. J. Nutr. 90: 993-995,
2003.
Figure 1. Percent of 2H5-22:5n-3
utilized for synthesis of 2H5-22:6n-3 in male ()
(n=5) and female ()
(n=5) subjects maintained on each of three different diets (ad-lib, beef-based,
and fish-based) for a period of three weeks.
Mean values (standard deviations as vertical bars) were derived from the
in vivo kinetic rate constants of n-3 fatty acid metabolism. The values were compared using the Student’s
t-test and the asterisk indicates a significant difference between males and
females when subjects were maintained on the beef diet (p = 0.03).
Alcohol amblyopia is a rare neuropathy
characterized by the development of blurred vision and a reduction in visual
acuity. A reciprocal change in the
DHA/DPAn-6 ratio is known to be associated with abnormal electroretinograms in
a number of species. Thus, a marginal intake of n-3 fatty acids in some alcohol
abusers may, in part, be responsible for the biochemical changes that underlie
the diminished retinal function associated with the visual abnormalities
observed in alcohol-amblyopic patients. Pawlosky RJ, Bacher J, Salem N Jr. Ethanol consumption alters electroretinograms and depletes
neural tissues of docosahexaenoic acid in rhesus monkeys: nutritional
consequences of a low n-3 fatty acid diet. Alcohol Clin Exp Res 2001 Dec;25(12):1758-65
Rhesus monkeys eating a diet containing
18:2n-6 and 18:3n-3 as 1.4 and 0.08% of the calories, respectively, plus
alcohol (mean 2.6 g kg(-1) d(-1)) had decreased amounts of 20:4n-6 and 22:6n-3
in their livers and plasma lipids compared with controls. Higher 2H5 enrichment in plasma 20:4n-6 and
22:6n-3, indicated that alcohol may have increased production of these fatty
acids. There was a greater concentration of 4-hydroxynonenal in the plasma of
alcohol-exposed monkeys compared to controls. Pawlosky RJ,
Rhesus monkeys maintained with low
levels of essential fatty acids (1.4 en% linoleic, 18:2n-6, and 0.08 en%,
linolenic acid, 18:3n-3) became depleted of 20:4n-6, and 22: 6n-3 in their
livers, plasma lipoproteins, and erythrocytes during an 18-month period of
alcohol exposure (2.6 g kg(-1) day(-1)). Monkeys that consumed alcohol also had
higher plasma concentrations of 4-hydroxynonenal compared to controls. The greater enrichment of deuterium in
biosynthesized 20:4n-6 and 22:6n-3 in the plasma of the monkeys exposed to
alcohol suggests a stimulation of the rate at which long-chain polyunsaturated
fatty acids are biosynthesized to compensate for an increase in lipid
peroxidation.
Pawlosky RJ,
Alcohol
Clin Exp Res 1999 Feb; 23(2):311-7.
Rhesus monkeys developed liver fibrosis
after consuming alcohol (mean, 2.6 g kg(-1) d[-1]) over a period of 3 years. In
the liver, plasma lipoproteins and erythrocytes, several polyunsaturated fatty
acids including 18:2n6, 20:4n6, and 22:6n3 were lower than in dietary controls.
The amount of alcohol consumed correlated positively with plasma lipid
peroxidation products, 4-hydroxynonenal (4-HNE) and 8-isoprostane F2alpha, and
negatively with 20:4n6 and 22:6n3 levels. Pawlosky RJ, Flynn BM,
Female domestic cats were acclimated to
one of six different defined diets 1 mo before mating and maintained on the
diets throughout pregnancy and lactation. Four diets contained only corn and
hydrogenated coconut oils as their source of fat in ratios of 1:9, 3:7, 6:4,
and 9:1, respectively. Two reference diets also contained the long-chain
polyunsaturated fatty acids arachidonate (20:4n-6) and docosahexaenoate
(22:6n-3). When the offspring were 8 wk old, electroretinograms showed that
animals raised in litters in which the maternal diets were devoid of 20:4n-6
and 22:6n-3 had higher a- and b-wave implicit times compared with the controls.
In the rod outer segments and brains of these animals, there were lower amounts
of 22:6n-3 and higher amounts of long-chain n-6 polyunsaturated fatty acids
compared with control animals. The findings suggest that maintenance of 22:6n-3
status in the nervous system is important for optimal retinal function in
juvenile cats. Pawlosky RJ, Denkins Y, Ward G,
Four adult female cats were acclimated
to a 10 weight% (wt%) fat diet consisting of 1 wt% corn oil and 9 wt%
hydrogenated coconut oil for 1 mo before mating. One female produced two live
offspring, and the other three females delivered either stillborn fetuses or
offspring that were severely deformed and died shortly after birth. Two of
these females were subsequently placed on a 1 wt% corn oil diet that was
supplemented with 20:4(n-6) (200 mg/ kg of diet), and after 2 mo they were mated.
Offspring resulting from the second mating were healthy. A third group of
females that were maintained on a 10 wt% fat diet consisting of 3 wt% corn oil
were also mated. The offspring from these matings appeared healthy at birth..
There were no differences in the level of 20:4(n-6) in the neonate brains among
any of the groups. Nutritional factors
unrelated to the tissue accumulation of arachidonic acid in the offspring may
be responsible for the high percentage of stillbirths and deformities
associated with maternal diets containing low amounts of essential fatty acids. Pawlosky RJ,
Rats and mice were dosed with
deuterium-labeled linoleic and linolenic acids either by intraperitoneal
injection or by gavage. Results demonstrated that the brain took up both
labeled essential fatty acids within 8 h from the time of dosing. Time-course
labeling experiments indicated that 20:5n-3 and 22:5n-3 may be converted to
22:6n-3 within the brain. A rise of labeled 22:6n-3 in the brain at 24 h
appeared to be due to uptake of this fatty acid from the blood. The amount of
labeled 22:6n-3 in the brain continued to increase beyond 24 h, and this did
not appear to be correlated with its blood concentration. These results suggest
that, during development in the rodent, different regions within the brain may
vary in their capacity to synthesize 22:6n-3, and this may be correlated with
regional growth rates. Pawlosky RJ, Ward G,
Alcohol altered the fatty acyl
composition of the liver, brain, and retina of domestic felines that were
maintained on a diet having low, but adequate, amounts of essential fatty
acids. For 8 mo, seven adult cats were provided a diet with 10% fat (by wt),
consisting of 9:1 ratio of hydrogenated coconut oil:corn oil. and four of the
cats were given oral daily doses of
ethanol (1.2 g.kg-1.d-1). In the
plasma and livers of the alcohol-exposed animals, there were significant
decreases in the concentrations of 18:2 omega 6, 20:4 omega 6, 22:5 omega 3,
and 22:6 omega 3 and increases in the concentrations of the nonessential fatty
acids 16:1 omega 7, 18:1 omega 9, and 20:3 omega 9. In the brains and retinas
of the alcohol-exposed animals, 22:6 omega 3 decreased by 17% and there was a
compensatory increase in 22:5 omega 6. In the retinas, the concentration of
22:5 omega 6 increased by 250%. The reciprocal change in the ratio of 22:6
omega 3 to 22:5 omega 6 is known to be associated with a loss in nervous system
function and may provide a biochemical mechanism underlying some of the
neuropathology associated with alcoholism. Pawlosky RJ,
Deuterated linoleic [18:2n-6
2H4-9,10,12,13] and linolenic [18:3n-3 2H5-17,17,18,18,18] acids were
chain-elongated and desaturated during incubations with rat liver homogenates.
The extracted fatty acids were converted to pentafluorobenzyl (PFB) esters and
analyzed by GC-MS (detection limit below 10 femtograms was more than three
orders of magnitude more sensitive than methyl ester derivatives). Isotope
ratios of the 2H4-18:2n-6 metabolites were used to quantify the deuterated
compounds from standard dilution curves generated from the ion abundances of
the unlabeled fatty acids. The 2H5-18:3n-3 metabolites were quantified
similarly using 18:3n-3. Pawlosky RJ, Sprecher HW,