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Title
Prevention of glomerular dysfunction in diabetic rats by treatment
with
d-alpha-tocopherol.
Author
Koya D; Lee IK; Ishii H; Kanoh H; King GL
Address
Research Division' Joslin Diabetes Center' Boston' MA 02215'
USA.
Source
J Am Soc Nephrol, 8(3):426-35 1997 Mar
Abstract
Because d-alpha-tocopherol (vitamin E) has been shown to decrease
diacylglycerol (DAG) levels and prevent the activation of protein
kinase C (PKC)' which is associated with retinal and renal dysfunctions
in diabetes' the study presented here characterized the effect
of
d-alpha-tocopherol treatment to prevent glomerular hyperfiltration
and
increased albuminuria as well as PKC activities in streptozotocin
(STZ)-induced diabetic rats. Two weeks after the induction of
diabetes'
total DAG content and PKC activity in glomeruli were significantly
increased in diabetic rats by 106.4 +/- 16.8% and 66.4 +/- 8.4%'
respectively' compared with control rats. Intraperitoneal inJection
of
d-alpha-tocopherol (40 mg/kg of body weight) every other day
prevented
the increases in total DAG content and PKC activity in glomeruli
of
diabetic rats. Glomerular filtration rate (GFR) and filtration
fraction
(FF) were significantly elevated to 4.98 +/- 0.34 mL/min and
0.36 +/-
0.05' respectively' in diabetic rats' compared with 2.90 +/-
0.14
mL/min and 0.25 +/- 0.02' respectively' in control rats. These
hemodynamic abnormalities in diabetic rats were normalized to
2.98 +/-
0.09 mL/min and 0.24 +/- 0.01' respectively' by d-alpha-tocopherol.
Albuminuria in 10-wk diabetic rats was significantly increased
to 9.1
+/- 2.2 mg/day compared with 1.2 +/- 0.3 mg/day in control rats'
whereas d-alpha-tocopherol treatment improved albumin excretion
rate to
2.4 +/- 0.6 mg/day in diabetic rats. To clarify the mechanism
of
d-alpha-tocopherol`s effect on DAG-PKC pathway' the activity
and
protein levels of DAG kinase alpha and gamma' which metabolize
DAG to
phosphatidic acid' were examined. Treatment with d-alpha-tocopherol
increased DAG kinase activity in the glomeruli of both control
and
diabetic rats' by 22.6 +/- 3.6% and 28.5 +/- 2.3% respectively'
although no differences were observed in the basal DAG kinase
activity
between control and diabetic rats. Because immunoblotting studies
did
not exhibit any difference in the protein levels of DAG kinase
alpha
and gamma' the effect of d-alpha-tocopherol is probably modulating
the
enzyme kinetics of DAG kinase. These findings suggest that the
increases in DAG-PKC pathway play an important role for the development
of glomerular hyperfiltration and increased albuminuria in diabetes
and
that d-alpha-tocopherol treatment could be preventing early changes
of
diabetic renal dysfunctions by normalizing the increases in DAG
and PKC
levels in glomerular cells.
Title
Bioavailability of various vitamin E compounds for finishing
swine.
Author
Anderson LE Sr; Myer RO; Brendemuhl JH; McDowell LR
Address
Animal Science Department' University of Florida' Gainesville
32611'
USA.
Source
J Anim Sci, 73(2):490-5 1995 Feb
Abstract
Relative bioavailabilities of four chemical forms of vitamin
E were
evaluated when supplemented in diets of finishing swine for 28
d. Forty
crossbred pigs (80 kg)' individually penned' were divided equally
among
five treatments. Treatments consisted of corn soybean meal-based
diets
supplemented with DL-alpha-tocopherol' DL-alpha-tocopheryl acetate'
D-alpha-tocopherol' or D-alpha-tocopheryl acetate. A treatment
without
vitamin E supplementation (negative control) served as the fifth
treatment. Each compound was supplemented at 62 IU/kg of diet.
Blood
samples were collected on d 0' 1' 2' 7' 14' 21' and 28. On d
29' half
the pigs were slaughtered to obtain tissue samples. Feed samples'
taken
from feeders' were also collected on d 0' 5' 14' and 21. All
vitamin E
forms fed increased (P < .01) serum alpha-tocopherol by d
2 and peaked
by d 7. Serum alpha-tocopherol in pigs fed either acetate form
remained
elevated beyond d 7; serum alpha-tocopherol steadily declined
and was
lower (P < .01) on d 14' 21' and 28 in pigs fed either alcohol
form
compared with concentrations in the acetate-fed pigs. The decrease
was
probably a reflection of poor stability of the alcohol forms
observed
in the feed; the acetate forms were found to be stable in the
feed over
the 28-d study. Dietary supplementation of D-alpha-tocopheryl
acetate
resulted in the highest serum alpha-tocopherol throughout the
study. A
similar trend was observed in tissue (liver' backfat' leaf fat'
semimembranosus' rhomboideus) alpha-tocopherol and serum: the
liver had
the highest concentration.(Abstract TRUNCATED AT 250 WORDS)
Title
Bioavailability of alpha-tocopherol fed with retinol and relative
bioavailability of d-alpha-tocopherol or DL-alpha-tocopherol
acetate.
Author
Eicher SD; Morrill JL; Velazco J
Address
Kansas State University' Manhattan 66506-1600' USA.
Source
J Dairy Sci, 80(2):393-9 1997 Feb
Abstract
Two experiments were conducted to examine the effects of the
form of
alpha-tocopherol or interactions of alpha-tocopherol with vitamin
A on
its bioavailability. In Experiment 1' Holstein steers were fed
a diet
that was low in vitamins A and E for 1 mo; then' steers were
blocked by
body weight (X = 97.5 kg) and assigned randomly to one of four
oral
treatments: 1) no added vitamins' 2) 442 mg of retinyl acetate'
3) 1342
mg of D-alpha-tocopherol' or 4) 442 mg of retinyl acetate and
1342 mg
of d-alpha-tocopherol. Each treatment was given as a pulse dose.
Blood
was sampled over a 36-h period. Concentrations of plasma retinyl
palmitate peaked at 2 to 6 h postsupplementation for all calves
and
then peaked again at 22 to 28 h for calves receiving vitamin
supplements. Concentrations of plasma alpha-tocopherol peaked
earliest
with d-alpha-tocopherol supplementation alone at 12 to 20 h after
supplementation' but simultaneous supplementation with retinyl
acetate
resulted in lower plasma alpha-tocopherol concentrations. Plasma
retinyl palmitate decreased during peak alpha-tocopherol
concentrations. In Experiment 2' blood and tissue were analyzed
after a
single gastric tube administration of a powder (DL-alpha-tocopheryl
acetate) or a liquid (d-alpha-tocopherol) form of vitamin E to
Holstein
calves. Plasma and kidney concentrations of alpha-tocopherol
were
higher when calves were fed d-alpha-tocopherol than when calves
were
fed the DL-alpha-tocopherol acetate form. Concentrations in the
liver'
spleen' adipose tissue' heart' muscle' cellular blood fraction'
and gut
did not differ between the two forms.
Title
d-alpha-tocopherol inhibition of vascular smooth muscle cell
proliferation occurs at physiological concentrations' correlates
with
protein kinase C inhibition' and is independent of its antioxidant
properties.
Author
Tasinato A; Boscoboinik D; Bartoli GM; Maroni P; Azzi A
Address
Institut f ur Biochemie und Molekularbiologie' Universit at Bern'
Switzerland.
Source
Proc Natl Acad Sci U S A, 92(26):12190-4 1995 Dec 19
Abstract
d-alpha-Tocopherol' but not d-beta-tocopherol' negatively regulates
proliferation of vascular smooth muscle cells at physiological
concentrations. d-alpha-tocopherol inhibits protein kinase C
(PKC)
activity' whereas d-beta-tocopherol is ineffective. Furthermore
d-beta-tocopherol prevents the inhibition of cell growth and
of PKC
activity caused by d-alpha-tocopherol. The negative regulation
by
d-alpha-tocopherol of PKC activity appears to be the cause and
not the
effect of smooth muscle cell growth inhibition. d-alpha-tocopherol
does
not act by binding to PKC directly but presumably by preventing
PKC
activation. It is concluded that' in vascular smooth muscle cells'
d-alpha-tocopherol acts specifically through a nonantioxidant
mechanism
and exerts a negative control on a signal transduction pathway
regulating cell proliferation.
Title
Urinary excretion of thiobarbituric acid reactive substances
of healthy
subJects supplemented with a high dose of d-alpha-tocopherol.
Author
Kosugi H; Asano Y; Nagayama T; Beppu M; Kikugawa K
Address
Ferris University' Yokohama' Japan.
Source
Biol Pharm Bull, 18(9):1275-8 1995 Sep
Abstract
The level of urinary thiobarbituric acid reactive substances
(TBARS)
consisting of bound forms of malonaldehyde and' to a lesser extent'
other aldehydes is one of the indices of lipid peroxidation status.
Levels of urinary TBARS in healthy subJects before and after
supplementation with a high dose of d-alpha-tocopherol were measured
using high performance liquid chromatography. Four healthy Japanese
were given a supplement of 300 mg d-alpha-tocopherol/d' about
40-fold
higher than the normal intake recommended' for a period of 50
d. Levels
of urinary TBARS (nmol/kg body weight.h) within-day' before and
after
supplementation with d-alpha-tocopherol' exhibited similar behavior
and
levels of daily urinary TBARS (nmol/kg body weight.d) were unchanged
by
d-alpha-tocopherol supplementation. These results indicate that
supplementation with a high dose of d-alpha-tocopherol does not
affect
the level of urinary TBARS.
Title
vitamin E prevents diabetes-induced abnormal retinal blood flow
via the
diacylglycerol-protein kinase C pathway.
Author
Kunisaki M; Bursell SE; Clermont AC; Ishii H; Ballas LM; Jirousek
MR;
Umeda F; Nawata H; King GL
Address
Research Division' Joslin Diabetes Center' Boston' Massachusetts'
USA.
Source
Am J Physiol, 269(2 Pt 1):E239-46 1995 Aug
Abstract
We have characterized effects of d-alpha-tocopherol (vitamin
E) on
activation of protein kinase C (PKC) and diacylglycerol (DAG)
levels in
retinal tissues of diabetic rats and correlated its effects to
diabetes-induced changes in retinal hemodynamics. Membrane PKC
specific
activities were increased by 71% in streptozocin-induced diabetic
rats
compared with controls (P < 0.05). Western blot analysis showed
that
membrane PKC-beta II was increased by 133 +/- 5% (P < 0.05).
InJection
of d-alpha-tocopherol (40 mg/kg ip) every other day prevented
the
increases in membrane PKC specific activity and PKC-beta II protein
by
immunoblots. Diabetes-induced increases in DAG levels were also
normalized by d-alpha-tocopherol treatment of 2 wk duration.
Physiologically' angiographic abnormalities of retinal hemodynamics
based on computerized video-based fluorescein angiography and
associated with increases of DAG and membranous PKC levels were
also
prevented by d-alpha-tocopherol treatment in diabetic rats. The
effect
of d-alpha-tocopherol on retinal vascular cells was also studied.
Exposure of retinal endothelial cells to 22 mM glucose for 3
days
increased total DAG and [3H palmitate-labeled DAG levels by 35
+/- 8
and 50 +/- 8% (P < 0.05)' respectively' compared with exposure
to 5.5
mM glucose. The presence of d-alpha-tocopherol (50 micrograms/ml)
prevented the increases in total DAG and [3H palmitate-labeled
DAG
levels in cells exposed to 22 mM glucose. These findings suggested
that
treatment with d-alpha-tocopherol can prevent diabetes-induced
abnormalities in rat retinal blood flow.(Abstract TRUNCATED AT
250
WORDS)
Title
Biodiscrimination of the eight alpha-tocopherol stereoisomers
results
in preferential accumulation of the four 2R forms in tissues
and plasma
of rats.
Author
Weiser H; Riss G; Kormann AW
Address
F. Hoffmann-La Roche Ltd' Vitamins and Fine Chemicals' Research
and
Technology Development' Basel' Switzerland.
Source
J Nutr, 126(10):2539-49 1996 Oct
Abstract
According to the USP' 2R'4`R'8`R-alpha-tocopheryl acetate
(RRR-alpha-TAc) is 1.36 times more active than all-rac-alpha-tocopheryl
acetate (all-rac-alpha-TAc). The all-rac form contains 12.5%
each of
the stereoisomers RRR' RRS' RSR' RSS' SSS' SSR' SRS and SRR'
which
display different biopotencies. In the present study' female
rats fed a
vitamin E-deficient diet were administered 0.82 mg of all-rac-alpha-TAc
or 0.60 mg of RRR-alpha-TAc daily for up to 90 d. alpha-Tocopherol
concentrations in liver' brain' adipose tissue and plasma were
not
significantly different among groups on treatment d 64 and 90.
Thus'
equipotent dosages of all-rac-alpha-TAc or RRR-alpha-TAc resulted
in
equimolar alpha-tocopherol plasma and tissue concentrations.
A
comparison with rats administered tocopherol-free placebo showed
that
plasma and tissue alpha-tocopherol of alpha-TAc-treated rats
represented alpha-tocopherol uptake during the repletion period.
The
eight individual alpha-tocopherol stereoisomers in tissues and
plasma
were determined by chiral HPLC and capillary gas chromatography.
Rats
treated with all-rac-alpha-TAc preferentially accumulated the
four 2R
alpha-tocopherol stereoisomers (15-22% each' sum of all 2R =
70-86%) in
tissues and plasma. The remaining 14-30% were 2S stereoisomers
with a
predominance of the SRS form. In conclusion' all-rac-alpha-TAc
administration led to the presence of all eight alpha-tocopherol
stereoisomers in rat liver' brain' adipose tissue and plasma.
The four
2R stereoisomers including RRR-alpha-tocopherol were equally
and
significantly enriched. This confirmed that the configuration
at C-2 of
the alpha-tocopherol molecule has a maJor impact on stereoisomer
biodiscrimination. Furthermore' the results are in agreement
with the
hypothesis that for alpha-tocopherol stereoisomers' biopotency
differences are related to corresponding differences of
alpha-tocopherol concentrations.
Title
alpha-Tocopheryl hemisuccinate administration increases rat liver
subcellular alpha-tocopherol levels and protects against carbon
tetrachloride-induced hepatotoxicity.
Author
Tirmenstein MA; Leraas TL; Fariss MW
Address
Department of Pharmaceutical Sciences' College of Pharmacy and
Graduate
Program in Pharmacology/Toxicology' Washington State University'
Pullman 99164-6510' USA.
Source
Toxicol Lett, 92(1):67-77 1997 Jun 16
Abstract
Rats were administered a series of tocopherol analogs 18 h prior
to a
hepatotoxic dose of carbon tetrachloride (CCl4). Of the compounds
tested' only d-alpha-tocopheryl hemisuccinate (TS) provided significant
protection against CCl4-induced hepatotoxicity. No protection
was
observed with either d-alpha-tocopherol (alpha-T) or a tocopherol
succinate ether derivative' d-alpha-tocopheryloxybutyric acid
(TSE).
None of the tocopherol analogs significantly inhibited CYP2E1
activity
as measured by oxidation of p-nitrophenol. Liver homogenates
and
subcellular fractions (cytosol' nuclei' plasma membranes' mitochondria
and microsomes) were collected 18 h after tocopherol analog
administration in the absence of CCl4. Homogenate and subcellular
alpha-T levels were not significantly increased following TSE
administration but were increased 2-3 fold following TS and alpha-T
administration. Total tocopherol levels (alpha-T+ TS + TSE) in
liver
homogenates and subcellular fractions were highest in rats supplemented
with TS. In these animals' TS was detected in all subcellular
fractions
and total tocopherol levels were increased from 6-23 fold over
those
seen in controls and 2-9 fold over alpha-T treated rats. In vitro
studies in which liver homogenates and subcellular fractions
were
peroxidized with ascorbate and ADP/Fe suggest that increasing
levels of
alpha-T but not TS correlates with increased protection against
lipid
peroxidation. These results suggest that the ability of TS to
protect
against CCl4-induced hepatotoxicity relates to its enhanced hepatic
accumulation and subsequent hydrolysis to alpha-T.
Title
alpha-Tocopherol and trolox block the early intracellular events
(TBARS
and calcium rises) elicited by oxidized low density lipoproteins
in
cultured endothelial cells.
Author
Mabile L; Fitoussi G; Periquet B; Schmitt A; Salvayre R;
N`egre-Salvayre A
Address
Department of Biochemistry' Faculty of Medicine in Rangueil'
University
Paul Sabatier' Toulouse' France.
Source
Free Radic Biol Med, 19(2):177-87 1995 Aug
Abstract
Low-density lipoproteins (LDLs)' treated by UV-C radiations under
conditions permitting mildly oxidized LDL (6 +/- 2 nmol TBARS/mg
apoB'
without maJor structural or functional alteration of apoB)' have
been
used for studying their cytotoxicity to cultured bovine aortic
endothelial cells and the cytoprotective effect of various analogs
of
alpha-tocopherol. Toxic doses of oxidized LDL evoked intracellular
events' such as cellular thiobarbituric acid reactive substances
(TBARS) and a sustained peak of [Ca2+ i (cytosolic calcium).
The
sustained [Ca2+ i peak seems to be directly involved in the genesis
of
cell inJury leading to cell death in contrast to cellular TBARS'
which
seems to be either an earlier step of signal transduction or
a side
effect' as shown by inhibiting the [Ca2+ i rise by ethylene
glycol-O'O`-bis(amino ethyl)-N1N1N`1N`-tetraacetic acid (EGTA)
added
Just before the time of the [Ca2+ i peak. When alpha-tocopherol
or
trolox (a short-chain' water-soluble analog of alpha-tocopherol)
were
added to the culture medium simultaneously with oxidized LDL'
they were
able to increase the resistance of endothelial cells against
the
cytotoxic effect of oxidized LDL' whereas alpha-tocopheryl acetate
and
alpha-tocopheryl succinate were almost completely ineffective
because
of the liberation of only very low levels of alpha-tocopherol.
Trolox
exhibited a more potent cytoprotective effect than alpha-tocopherol
(IC50: 1 +/- 0.2 and 8 +/- 2 mumol/l for trolox and alpha-tocopherol'
respectively). As shown by preincubating cells with effective
concentrations of alpha-tocopherol or trolox' the cytoprotective
effect
was completely independent of any inhibition of LDL oxidation
and was
remanent for 2 d with alpha-tocopherol or for 3-4 d with trolox.
Cytoprotective concentrations of trolox and alpha-tocopherol
did not
inhibit LDL uptake but acted at the cellular level by blocking
the
formation of cellular TBARS and the sustained [Ca2+ i peak as
well. The
potential relevance of these data in relation to the prevention
of
atherosclerosis is discussed.
Title
Vitamin C nutriture has little short-term effect on vitamin E
concentrations in healthy women.
Author
Jacob RA; Kutnink MA; Csallany AS; Daroszewska M; Burton GW
Address
Western Human Nutrition Research Center' U.S. Department of
Agriculture' Agricultural Research Service' Presidio of San Francisco'
CA 94129' USA.
Source
J Nutr, 126(9):2268-77 1996 Sep
Abstract
To determine whether the postulated sparing effect of vitamin
E by
ascorbic acid (AA) is important for human nutrition' we studied
vitamin
E status in 20 healthy pre-menopausal women (age 20-43 y) with
high or
low vitamin C intakes for 6 wk in a live-in metabolic unit. The
experimental diet contained no fruits and vegetables and provided
5
mg/d of AA (Recommended Dietary Allowance = 60 mg/d)' 3 mg/d
of
alpha-tocopherol (RDA = 10 mg/d) and 42 g/d of tocopherol-stripped
safflower oil to increase the vitamin E requirement. Half of
the
subJects revived a daily AA supplement of 495 mg (high AA group).
A
biochemical ascorbate deficiency was attained in the low AA group
as
indicated by plasma AA concentrations that reached the lower
limit of
normal by study d 15. Oral doses (20 mg) of hexadeuterated
RRR-alpha-tocopherol acetate (d6-alphaT) were given daily to
all
subJects on d 15-21. Measures of vitamin E status included d6-alphaT
and unlabeled alpha-tocopherol concentrations in plasma' platelets'
buccal cells and adipose. The levels of unlabeled alpha-tocopherol
decreased over time in plasma and platelets and were unchanged
for
buccal cells and adipose' but were not significantly affected
by AA
intake. Likewise' the rise and fall of plasma and platelet d6-alpha
T'
and measures of lipid peroxidation' were not affected by AA intake.
Although vitamin C nutriture did not significantly affect vitamin
E
status within the 6-wk time period of this experiment' further
study of
this question is warranted' because some of the present results
indicate a trend toward sparing of tissue tocopherol by high
AA intake.
Title
Efficacy of dietary and inJected vitamin E for poults.
Author
Soto-Salanova MF; Sell JL
Address
Department of Animal Science' Iowa State University' Ames 50011-3150'
USA.
Source
Poult Sci, 75(11):1393-403 1996 Nov
Abstract
An experiment was conducted to compare the efficacy of two dietary
sources and an inJectable form of vitamin E (VE) to improve the
VE
status of poults. Six of the treatments consisted of a factorial
arrangement of three concentrations and two sources of dietary
VE.
Turkeys in these treatments received 12' 80' or 150 IU of either
dl-alpha-tocopheryl acetate or d-alpha-tocopherol (d-alpha-TOC)/kg
of
diet. The seventh treatment consisted of a single subcutaneous
inJection of d-alpha-TOC at 1 d of age. Poults in this treatment
were
subcutaneously inJected in the dorsal area of the neck with 25
IU of
d-alpha-TOC' this amount being approximately equivalent to the
amount
poults would consume if their diet was supplemented with 150
IU of
VE/kg during their 1st wk of life. Concentration' source' or
route of
VE administration did not affect growth parameters' plasma creatine
kinase' plasma triglycerides' or liver lipid peroxidation as
measured
by the thiobarbituric acid reactive substances assay (TBARS).
Plasma'
red blood cells (RBC)' and liver alpha-TOC decreased from hatching
to
14 d of age in poults fed either Source of VE. The use
of 80 or 150 IU
of dietary VE (either Source) reduced (P < 0.05) the
extent of
depletion of alpha-TOC at all ages and also reduced the susceptibility
of RBC to hemolysis. There was no effect of Source of
dietary VE on
concentration of alpha-TOC in plasma' RBC' or liver' or on RBC
hemolysis. Subcutaneous inJection of 25 IU of d-alpha-TOC at
Day 1
increased (P < 0.05) alpha-TOC concentration until 7 d of
age. Also'
d-alpha-TOC inJection reduced (P < 0.05) RBC susceptibility
to
hemolysis through 21 d of age. Data showed that one single subcutaneous
inJection of 25 IU of d-alpha-TOC at 1 d of age was as effective
as 80
IU or more of dietary VE through 21 d to improve the alpha-TOC
status
of poults.
Title
Tocopherols and 6-hydroxy-chroman-2-carbonitrile derivatives
inhibit
vascular smooth muscle cell proliferation by a nonantioxidant
mechanism.
Author
Boscoboinik D; Ozer NK; Moser U; Azzi A
Address
Institut f ur Biochemie und Molekularbiologie' Universit at Bern'
Switzerland.
Source
Arch Biochem Biophys, 318(1):241-6 1995 Apr 1
Abstract
The effects of two groups of similar compounds' a series of tocopherols
and one of 6-hydroxy-chroman-2-carbonitrile' have been studied
in
vascular smooth muscle cells. A poor correlation has been found
between
antiproliferative and antioxidant properties of these molecules.
d-alpha-tocopherol inhibits cell proliferation' while
D-alpha-tocopherylquinone has been found neither to inhibit nor
to
activate. D-beta-Tocopherol' a poor inhibitor of smooth muscle
cell
proliferation' has been shown to be capable of preventing and
reversing
the inhibition by d-alpha-tocopherol. It is concluded that the
tocopherols and carbonitrile derivatives tested here appear to
inhibit
smooth muscle cell proliferation by a nonantioxidant mechanism.
The
competition between d-alpha-tocopherol and D-beta-tocopherol
suggests
the existence of a common binding site for the two molecules. |
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