(Circulation. 2000;102:539.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Effects of Vitamin E Supplementation on F2-Isoprostane and Thromboxane Biosynthesis in Healthy Cigarette Smokers
From the Departments of Medicine and Aging (P.P., M.R.P., S.T., F.S., A.M., G.S., M.G.S., F.C., G.D., C.P.) and Biomedical Sciences (T.B.), University of Chieti G. D’Annunzio School of Medicine, Chieti; Department of Pharmacology, Catholic University School of Medicine, Rome (G.C.); and Division of Internal Medicine, Venice General Hospital, Venice (P.A., P.G., G.B.B.), Italy.
Correspondence to Paola Patrignani, PhD, Cattedra di Farmacologia I, Dipartimento di Medicina e Scienze dell’Invecchiamento, Università di Chieti G. D’Annunzio, c/o Palazzina delle Scuole di Specializzazione, Via dei Vestini 31, 66013 Chieti, Italy. E-mail ppatrignani{at}unich.it
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Abstract |
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Background—Increased formation of 8-iso-prostaglandin (PG) F2
and
thromboxane (TX) A2, potent agonists of
platelet and vascular thromboxane (TH)/PGH2
receptors, has been detected in cigarette smokers. We performed
a randomized, double-blind, placebo-controlled study of the effects of
vitamin E (300, 600, and 1200 mg/d, each dose for 3 consecutive weeks)
on 8-iso-PGF2 and TXA2 biosynthesis in 46
moderate cigarette smokers.
Methods and Results—Urinary immunoreactive
8-iso-PGF2 and 11-dehydro-TXB2, plasma
vitamin E, and serum TXB2 were measured by previously
validated techniques. Baseline urinary 8-iso-PGF2 and
11-dehydro-TXB2 excretion averaged 241±78 and 430±293
pg/mg creatinine, respectively. Urinary
8-iso-PGF2 was significantly correlated with
11-dehydro-TXB2 (r=0.360, n=138,
P<0.0001). Baseline plasma vitamin E levels averaged
20.6±4.9 µmol/L and were inversely correlated with urinary
11-dehydro-TXB2 (r=-0.304,
P=0.039) but not with 8-iso-PGF2
(r=-0.227, P=0.129). Vitamin E
supplementation caused a dose-dependent increase in its plasma levels
that reached a plateau at 600 mg (42.3±11.2 µmol/L,
P<0.001). This was not associated with any
statistically significant change in urinary 8-iso-PGF2
or 11-dehydro-TXB2 excretion.
Conclusions—Supplementation with pharmacological doses of vitamin E has no detectable effects on lipid peroxidation and thromboxane biosynthesis in vivo in healthy subjects with a mild degree of oxidant stress. These findings are consistent with the hypothesis that the basal rate of lipid peroxidation is a major determinant of the response to vitamin E supplementation and have implications for the use of vitamin E in healthy subjects as well as for the design and interpretation of clinical trials of antioxidant intervention.
Key Words: prostaglandins • thromboxane • vitamins • smoking • lipids
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Vitamin E (
-tocopherol) is thought to have
a role in the prevention of atherosclerosis through
inhibition of oxidative modifications of LDLs.1 2 Although
observational studies suggest an inverse correlation between the intake
of antioxidants, such as vitamin E and ß-carotene, and the incidence
of coronary heart disease, clinical trials of antioxidant
supplementation in patients with ischemic heart disease have
yielded apparently conflicting results.3 4 5 This may
reflect, at least in part, the variable dose and duration of
vitamin E supplementation as well as the oxidant/antioxidant balance of
the different patient populations entered into the trials. Moreover,
the inconsistency of trial results probably reflects the
inadequacy of traditional indices of lipid peroxidation in guiding the
selection of the appropriate dose of vitamin E to be tested in
humans.6
A novel analytical approach to quantify the antioxidant effect
of vitamin E in vivo is provided by measurements of
F2-isoprostanes in plasma and urine.
F2-isoprostanes are formed nonenzymatically
through free radical–catalyzed attack on esterified
arachidonic acid, followed by their enzymatic release
from cellular or lipoprotein phospholipids (reviewed in References
7 , 8 , and 9 ).
F2-isoprostanes circulate in plasma at low
concentrations and are excreted in urine.
8-iso-Prostaglandin (PG) F2 (also
referred to as iPF2-III10 ) is an
abundant F2-isoprostane formed in vivo in
humans.7 8 9 This compound is of particular interest
because it induces vasoconstriction11 and modulates the
function of human platelets12 13 through the
interaction with receptors that are distinct from but closely related
to thromboxane (TX)
A2/PGH2 receptors.
Enhanced formation of F2-isoprostanes has been reported in association with several cardiovascular risk factors, including hypercholesterolemia,14 15 diabetes mellitus,16 and cigarette smoking,17 18 that are characterized by increased lipid peroxidation in response to complex metabolic abnormalities or various constituents of cigarette smoke.
In both hypercholesterolemic14 and diabetic16 patients, 2-week supplementation with pharmacological doses of vitamin E (600 mg/d) was associated with normalization of enhanced F2-isoprostane formation. Similar findings were reported in apolipoprotein E–deficient mice with a long-term dosing regimen of vitamin E.19
In contrast, the short-term administration of vitamin E (100 and 800
IU/d for 5 days) to healthy chronic smokers failed to suppress urinary
8-iso-PGF2 excretion, and administration of
vitamin C (2 g/d), alone or in combination with vitamin E, only
partially reduced isoprostane excretion (by 
20% to
30%).18 Factors that may account for this apparent
discrepancy include the small sample size (5 to 7 subjects), short
duration of vitamin E supplementation (5 days), and lack of placebo
control in this study.18 Alternatively, the different
rates of lipid peroxidation associated with cigarette smoking versus
hypercholesterolemia and diabetes mellitus
might represent an important determinant of the variable
effects of vitamin E supplementation in these settings. Resolving this
apparent discrepancy might have implications for the interpretation of
the results of recently completed clinical trials of antioxidant
intervention, such as GISSI-Prevenzione4 and the Heart
Outcomes Prevention Evaluation Study.5 Thus, we designed a
randomized, placebo-controlled, double-blind dose-finding study of the
effects of vitamin E supplementation on lipid peroxidation in moderate
cigarette smokers with adequate statistical power to detect a small
effect on urinary 8-iso-PGF2 excretion and
sufficient duration to achieve steady-state plasma levels of vitamin E.
Moreover, we examined the rate of TXA2
biosynthesis in vivo as a biological readout of changes in
F2-isoprostane formation associated with vitamin
E supplementation.
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Methods |
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Clinical Study Design
Forty-eight apparently healthy volunteers (30 male and 18 female subjects, 20 to 47 years old) who had smoked 15 to 30 cigarettes per day during the previous 2 years were recruited to participate in a randomized, double-blind, placebo-controlled trial of vitamin E (d,l-
-tocopheryl acetate; Bayer SpA) supplementation.
None of the subjects were taking any medication, including vitamins.
During the first week of the study, the 48 smokers were screened for
the inclusion and exclusion criteria of the study; during the following
3 weeks, repeated blood and urinary samples were collected for
evaluation of the reproducibility of urinary
8-iso-PGF2 and plasma vitamin E levels; then,
subjects were randomized to receive placebo or vitamin E 300, 600, or
1200 mg/d for 3 consecutive weeks; after completion of the treatment
period, there was a washout period of 3 weeks to assess the time course
of recovery. Two volunteers dropped out after the first week of
treatment because of the onset of viral infection and were not
replaced. Peripheral venous blood and urinary samples were
collected weekly throughout the 9-week duration of the study. Urinary
excretion of 8-iso-PGF2 was the primary end
point of the study. We assessed compliance with the study medication as
well as achievement of steady state through repeated measurement of
vitamin E in plasma. To control for variable exposure to cigarette
smoking among the 4 treatment groups at baseline and during the
randomized phase of the study, we measured the urinary excretion of
cotinine, a nicotine metabolite, weekly. We also evaluated the effects
of vitamin E supplementation on the biosynthesis of
TXA2 ex vivo20 and in
vivo21 to explore the relationship between oxidant stress
and platelet activation in the setting of chronic cigarette
smoking. The protocol of the study was approved by the institutional
review committees of the medical centers involved, and informed consent
was obtained from all subjects.
Peripheral blood samples were drawn at 10 AM,
and 1-mL aliquots were immediately transferred into glass tubes and
allowed to clot at 37°C for 1 hour. Serum was separated by
centrifugation and kept at -30°C until assayed for
TXB2 as a reflection of maximally stimulated
cyclooxygenase activity of platelet PGH
synthase-1 by endogenously formed thrombin.20
Eight-hour urine samples (11 PM to 7 AM)
were collected, the timing and total volume were recorded, and two
50-mL aliquots were stored at -70°C until extraction. To prevent the
formation of 8-iso-PGF2 in vitro, 1
mmol/L of the antioxidant 4-hydroxy-Tempo (Sigma Chemical Co) was added
to 1 aliquot of each urine sample.
Analyses of Eicosanoids and F2-Isoprostanes
Immunoreactive serum TXB2 and urinary
8-iso-PGF2 and
11-dehydro-TXB2 were measured by previously
validated radioimmunoassay techniques.20 21 22 23 All urinary
measurements were corrected for recovery and creatinine
excretion.
Other Biochemical Analyses
Cotinine was measured by radioimmunoassay
(Diagnostic Products Corp) after extraction from 10-mL
aliquots of each urine sample on Sep-Pak C18
cartridges (Waters Associates) and elution with chloroform/isopropanol
(85/15, vol/vol).24 Plasma vitamin E was measured by
reversed-phase high-performance liquid
chromatography.25
Statistical Analysis
With a sample size of 12 subjects per arm, the study had an 85%
power (1-ß) to detect a 35% difference in urinary
8-iso-PGF2 between placebo and vitamin E, with
=0.05. Statistical comparisons were made by ANOVA, and significant
differences between treatments were determined by the
Student-Newman-Keuls test. The Pearson coefficient (r) was
calculated to quantify the direction and magnitude of correlation
between variables, and linear regression was used to find the line
that best predicts y from x. All data were
expressed as mean±SD. A probability value of P<0.05 was
assumed to be statistically significant.
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Results |
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The baseline measurements obtained in the 46 healthy cigarette smokers who completed the study are detailed in the Table
. Only minor differences were
noted in blood lipid levels among the different groups.
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Urinary cotinine excretion, a sensitive marker of exposure to cigarette
smoking,26 averaged 2394±1454 ng/mg
creatinine (n=138) throughout the study and was comparable
in the 4 treatment groups at baseline. As shown in Figure 1, the administration of vitamin E did
not affect the urinary excretion of cotinine to any statistically
significant extent, nor was any appreciable time-related change
measured in the placebo arm of the study.
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Baseline plasma levels of vitamin E averaged 20.6±4.9 µmol/L
(n=46) and were comparable in the 4 treatment groups (Table
). As
shown in Figure 2, vitamin E
supplementation was associated with dose-dependent increases in its
plasma levels that reached a plateau at 600 mg (placebo, 21.9±7.7
µmol/L; and vitamin E 300 mg/d, 33±9.2 µmol/L; 600 mg/d,
42.3±11.2 µmol/L; and 1200 mg/d, 42.7±15.3 µmol/L;
P<0.001 versus baseline and versus placebo) and returned to
pretreatment levels during the washout period of the study. A
comparison of vitamin E concentrations measured repeatedly during the 3
weeks of supplementation clearly demonstrates achievement of
steady-state plasma levels during the treatment period of the study
(Figure 2).
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Baseline urinary 8-iso-PGF2 averaged 241±78
pg/mg creatinine (n=46) and was not significantly different
among the 4 treatment groups (Table). In the placebo-treated
subjects, urinary 8-iso-PGF2 excretion,
assessed throughout the 9 weeks of the study, averaged 233±130 pg/mg
creatinine (n=107) (intrasubject coefficient of variation,
33±11%, n=12). No statistically significant correlation was found
between the excretion rate of 8-iso-PGF2 and
plasma levels of vitamin E evaluated at baseline (r=-0.227,
n=46, P=0.129; Figure 3A).
Increased availability of vitamin E, produced by supplementation with
300, 600, and 1200 mg/d for 3 weeks, was not associated with any
statistically significant change in urinary
8-iso-PGF2 excretion (Figure 4). The urinary excretion of
8-iso-PGF2 and plasma levels of vitamin E
measured throughout the 9 weeks of the study showed no statistically
significant correlation (r=-0.065, n=138,
P=0.452).
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We also evaluated the potential impact of vitamin E supplementation on
the maximal biosynthetic capacity of circulating platelets, as
reflected by measurements of TXB2
production during whole-blood clotting,20 as well
as on the actual rate of TXA2 biosynthesis in
vivo, as reflected by the urinary excretion of its major metabolite,
11-dehydro-TXB2.21 Serum
TXB2 averaged 564±128 ng/mL (n=46) at baseline
and was not affected by supplementation with vitamin E up to 1200 mg/d
to any statistically significant extent (data not shown). Urinary
11-dehydro-TXB2 averaged 430±293 pg/mg
creatinine (n=46) at baseline. As shown in Figure 3B, urinary 11-dehydro-TXB2 excretion
rates correlated inversely with plasma vitamin E levels
(r=-0.304, n=46, P=0.039). A trend for baseline
urinary 11-dehydro-TXB2 to correlate with urinary
8-iso-PGF2 was apparent, but this relationship
failed to attain conventional statistical significance
(r=0.285, n=46, P=0.054; Figure 5A). However, the Pearson correlation
coefficient for urinary excretion rates of
11-dehydro-TXB2 and
8-iso-PGF2, measured throughout the 9 weeks of
the study, was statistically significant (r=0.360, n=138,
P<0.0001; Figure 5B).
11-dehydro-TXB2 excretion remained substantially
unchanged during vitamin E supplementation (Figure 6).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The measurement of F2-isoprostane formation in vivo is currently accepted as a useful tool for identifying populations that may have enhanced rates of lipid peroxidation.27 In fact, elevated levels of F2-isoprostanes have been observed in plasma and urine of animals and humans under a wide variety of conditions of enhanced oxidative stress.14 15 16 17 18 19 The finding of increased levels of F2-isoprostanes both in the circulation and in the urine of persons who smoke17 18 is consistent with the notion that cigarette smoke contains a large number of oxidants and free radicals that could directly initiate and propagate the process of lipid peroxidation.28
As reported by Reilly et al,18 a dose-response
relationship exists between the number of cigarettes smoked and the
urinary excretion of 8-iso-PGF2. Thus, in
moderate (15 to 30 cigarettes per day) and heavy (>30 cigarettes per
day) smokers, the urinary excretion of
8-iso-PGF2 averaged 290 and 550 pg/mg
creatinine, respectively. In the moderate chronic smokers
participating in the present study, the urinary excretion of
8-iso-PGF2 averaged 241±78 pg/mg
creatinine (n=46), consistent with the results of
Reilly et al.18
Enhanced lipid peroxidation in cigarette smokers may be related to
antioxidant depletion that could be restored by antioxidant
supplementation. In a short-term study, the administration of vitamin C
(2 g/d for 5 consecutive days) alone or in combination with vitamin E
(800 IU/d) to chronic cigarette smokers resulted in a statistically
significant (20% to 30%) decline in
F2-isoprostane excretion.18 In
contrast, supplementation with vitamin E alone, 100 IU/d (in moderate
smokers) or 800 IU/d (in heavy smokers), failed to significantly affect
the urinary excretion of
8-iso-PGF2.18 Failure of vitamin
E to suppress isoprostane biosynthesis in this study18
might be related to the doses administered, the small sample size, or
the short duration of the study. Thus, using
8-iso-PGF2 excretion as the primary end point
of the study, we set out to investigate the time- and dose-dependence
of the antioxidant effects of vitamin E supplementation in chronic
cigarette smokers.
The administration of vitamin E caused a dose-dependent increase in its
plasma levels that reached steady state during the 3-week treatment
study. A maximum 2-fold increase was detected during the administration
of 600 mg/d of vitamin E. We have previously described a similar 2-fold
increase in plasma vitamin E concentrations by supplementation with 600
mg/d in patients with type IIa
hypercholesterolemia14 and in
patients with type II diabetes mellitus.16 This is in
agreement with previous studies showing that large doses of
supplemental vitamin E do not increase circulating vitamin E
concentrations more than 3-fold.29 This is probably not
due to limitation of vitamin E absorption but rather to the fact that
newly absorbed vitamin E in part replaces -tocopherol in
circulating lipoproteins.30 31 In fact, >50% of the
variation in plasma -tocopherol is explained by plasma
cholesterol and triacylglycerol
concentrations.32
Supplementation with pharmacological doses of vitamin E up to 1200 mg/d
was not associated with any detectable change in urinary
8-iso-PGF2 excretion in the present study.
Several factors might contribute to this negative finding. These
include (1) a type II error due to inadequate sample size, (2)
noncompliance with the study medication, and (3) lack of
specificity of the analytical signal. In fact, given the
intraindividual variability of urinary
8-iso-PGF2 excretion on repeated sampling, our
study had 85% power to detect a 35% change in this biochemical end
point with =0.05. Detection of a smaller change in
F2-isoprostane formation would require a much
larger sample size and would probably be meaningless. Noncompliance
with the study medication seems unlikely in view of the
consistent changes in vitamin E levels (Figure 2). The
specificity of the radioimmunological measurement of
8-iso-PGF2 might be questioned. However, the
assay was previously validated by comparison with gas
chromatography/mass spectrometry23 and has
been used extensively to demonstrate changes in
F2-isoprostane formation in studies of similar
sample size and duration in the setting of
hypercholesterolemia,14
non–insulin-dependent diabetes mellitus,16 and cystic
fibrosis.33 The daily administration of 600 mg of vitamin
E for 2 weeks to hypercholesterolemic and diabetic
patients was associated with statistically significant reductions in
8-iso-PGF2 excretion by 58% and 37%,
respectively (References 14 and 16
and Figure 7A). The same dose of vitamin
E as administered to patients with cystic fibrosis significantly (by
42%) reduced the excretion rate of 8-iso-PGF2
(Figure 7A). Taken together, these data suggest that the same
pharmacological dose of vitamin E may have variable antioxidant
effects in different patient populations characterized by variable
rates of lipid peroxidation. Moreover, the finding of a linear
correlation between the basal rate of
8-iso-PGF2 excretion and the slope of changes
in this index of lipid peroxidation as a function of changes in plasma
vitamin E associated with short-term dosing with 600 mg/d in different
clinical settings (Figure 7B) is consistent with the
hypothesis that the basal rate of lipid peroxidation is a major
determinant of the response to vitamin E supplementation.
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Further evidence for unchanged levels of biologically active
isoprostanes during vitamin E supplementation in the present study
can be found in the lack of detectable changes in the rate of
TXA2 biosynthesis in vivo.
F2-isoprostanes and other biologically active
isoeicosanoids can amplify the platelet response to other agonists
in vitro.12 13 Consistent with this concept,
persistent changes in the rate of F2-isoprostane
formation, as detected in patients with metabolic
disorders,14 16 are associated with concordant changes in
the rate of TXA2 biosynthesis in vivo. Thus, we
have suggested that F2-isoprostane formation may
provide an important biochemical link between oxidant stress and
platelet activation in these settings.14 16 A similar
link is apparent in the present study, although the correlation
between urinary excretion rates of 8-iso-PGF2
and 11-dehydro-TXB2 is much weaker (Figure 5) than in earlier studies of
hypercholesterolemia14 and
diabetes mellitus.16 The failure of vitamin E
supplementation to reduce thromboxane metabolite excretion
in healthy cigarette smokers in the present study provides
important support to our contention14 16 that vitamin E
may blunt F2-isoprostane–mediated amplification
of platelet activation in other clinical settings, such as those
depicted in Figure 7, rather than exerting a direct
antiplatelet effect.
The overall picture emerging from a series of studies,14 16 18 19 as well as the present study, of vitamin E supplementation using the in vivo formation of F2-isoprostanes as the primary biochemical end point suggests that the effect of vitamin E on lipid peroxidation cannot be equated to that of a conventional drug blocking an enzyme or receptor in a reproducible fashion in the vast majority of patients exposed to treatment. Most likely, both the mechanism(s) responsible for enhanced oxidant stress and the rate of lipid peroxidation are important determinants of the antioxidant effects of vitamin E supplementation. This hypothesis may help in interpreting the conflicting and largely disappointing results of recently completed trials of vitamin E supplementation in patients with ischemic heart disease.3 4 5 Any protective effect of antioxidant intervention that is readily apparent in the setting of genetically determined enhanced lipid peroxidation19 is likely to be diluted by inclusion of a large proportion of patients with low levels of lipid peroxidation because of dietary habits (such as in the GISSI-Prevenzione Study, carried out in the setting of a largely Mediterranean diet4 ) or lack of metabolic abnormalities associated with oxidant stress.
In conclusion, the present findings may have practical implications for the use of vitamin E supplements for cardiovascular prevention in the general population. Moreover, they suggest the need to reevaluate the response of potential target populations based on noninvasive measurements of F2-isoprostane formation as a rational basis for a new trial design.
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Acknowledgments |
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This study was supported by grants from Bayer Italia SpA and the Ministero dell’Università e Ricerca Scientifica e Tecnologica (9706570507-005). We wish to thank Dr Simonetta Pignattelli for generous organizational support and Daniela Basilico for expert editorial assistance.
Received December 29, 1999; revision received March 4, 2000; accepted March 8, 2000.
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L. O Dragsted, A. Pedersen, A. Hermetter, S. Basu, M. Hansen, G. R Haren, M. Kall, V. Breinholt, J. J. Castenmiller, J. Stagsted, et al. The 6-a-day study: effects of fruit and vegetables on markers of oxidative stress and antioxidative defense in healthy nonsmokers Am. J. Clinical Nutrition, June 1, 2004; 79(6): 1060 - 1072. [Abstract] [Full Text] [PDF]
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J. E Upritchard, C. R. Schuurman, A. Wiersma, L. B. Tijburg, S. A. Coolen, P. J Rijken, and S. A Wiseman Spread supplemented with moderate doses of vitamin E and carotenoids reduces lipid peroxidation in healthy, nonsmoking adults Am. J. Clinical Nutrition, November 1, 2003; 78(5): 985 - 992. [Abstract] [Full Text] [PDF]
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C. Sanchez-Moreno, M P. Cano, B. de Ancos, L. Plaza, B. Olmedilla, F. Granado, and A. Martin Effect of orange juice intake on vitamin C concentrations and biomarkers of antioxidant status in humans Am. J. Clinical Nutrition, September 1, 2003; 78(3): 454 - 460. [Abstract] [Full Text] [PDF]
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C. Sanchez-Moreno, M. P. Cano, B. de Ancos, L. Plaza, B. Olmedilla, F. Granado, and A. Martin High-Pressurized Orange Juice Consumption Affects Plasma Vitamin C, Antioxidative Status and Inflammatory Markers in Healthy Humans J. Nutr., July 1, 2003; 133(7): 2204 - 2209. [Abstract] [Full Text] [PDF]
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J. V. Higdon and B. Frei Obesity and Oxidative Stress: A Direct Link to CVD? Arterioscler Thromb Vasc Biol, March 1, 2003; 23(3): 365 - 367. [Full Text] [PDF]
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D. J O'Byrne, S. Devaraj, S. M Grundy, and I. Jialal Comparison of the antioxidant effects of Concord grape juice flavonoids {alpha}-tocopherol on markers of oxidative stress in healthy adults Am. J. Clinical Nutrition, December 1, 2002; 76(6): 1367 - 1374. [Abstract] [Full Text] [PDF]
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R. De Caterina, F. Cipollone, F. P. Filardo, M. Zimarino, W. Bernini, G. Lazzerini, T. Bucciarelli, A. Falco, P. Marchesani, R. Muraro, et al. Low-Density Lipoprotein Level Reduction by the 3-Hydroxy-3-Methylglutaryl Coenzyme-A Inhibitor Simvastatin Is Accompanied by a Related Reduction of F2-Isoprostane Formation in Hypercholesterolemic Subjects: No Further Effect of Vitamin E Circulation, November 12, 2002; 106(20): 2543 - 2549. [Abstract] [Full Text] [PDF]
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 G. Davi, M. T. Guagnano, G. Ciabattoni, S. Basili, A. Falco, M. Marinopiccoli, M. Nutini, S. Sensi, and C. Patrono Platelet Activation in Obese Women: Role of Inflammation and Oxidant Stress JAMA, October 23, 2002; 288(16): 2008 - 2014. [Abstract] [Full Text] [PDF]
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J.-L. Cracowski, F. Stanke-Labesque, G. Bessard, H. Tsutsui, T. Ide, A. Takeshita, and N. Ohashi Physiological Variations of Isoprostanes: A Step Forward? * Physiological Variations of Isoprostanes: A Step Forward? Response to Letter to the Editor Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): 1239 - 1241. [Full Text]
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J. M. Hodgson, K. D. Croft, T. A. Mori, V. Burke, L. J. Beilin, and I. B. Puddey Regular Ingestion of Tea Does Not Inhibit In Vivo Lipid Peroxidation in Humans J. Nutr., January 1, 2002; 132(1): 55 - 58. [Abstract] [Full Text] [PDF]
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J. W. Heinecke Is the Emperor Wearing Clothes?: Clinical Trials of Vitamin E and the LDL Oxidation Hypothesis Arterioscler Thromb Vasc Biol, August 1, 2001; 21(8): 1261 - 1264. [Abstract] [Full Text] [PDF]
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R. B. Weinberg, B. S. VanderWerken, R. A. Anderson, J. E. Stegner, and M. J. Thomas Pro-Oxidant Effect of Vitamin E in Cigarette Smokers Consuming a High Polyunsaturated Fat Diet Arterioscler Thromb Vasc Biol, June 1, 2001; 21(6): 1029 - 1033. [Abstract] [Full Text] [PDF]
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E. A. Meagher, O. P. Barry, J. A. Lawson, J. Rokach, and G. A. FitzGerald Effects of Vitamin E on Lipid Peroxidation in Healthy Persons JAMA, March 7, 2001; 285(9): 1178 - 1182. [Abstract] [Full Text] [PDF]
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A. S. Whitehead and G. A. FitzGerald Twenty-First Century Phox: Not Yet Ready for Widespread Screening Circulation, January 2, 2001; 103(1): 7 - 9. [Full Text] [PDF]
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