(Circulation. 1996;94:19-25.)
© 1996 American Heart Association, Inc.
Articles |
Modulation of Oxidant Stress In Vivo in Chronic Cigarette Smokers
Presented in part at the annual meeting of the American Society for Clinical Investigation, Washington, DC, May 1994, and at the Ninth International Conference on Prostaglandins and Related Compounds, Florence, Italy, August 1994.
From the Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia.
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Abstract |
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Background Free radical–induced oxidative damage is thought to be involved in the pathogenesis of diseases associated with cigarette smoking. We examined the production of 8-epi-prostaglandin (PG) F2
, a stable product of lipid
peroxidation in vivo, and its modulation by aspirin and antioxidant
vitamins in chronic cigarette smokers.
Methods and Results We performed the following studies: (1)
a cross-sectional comparison of smokers and control subjects, (2)
an examination of the dose-response relationship, (3) an
exploration of the effect of smoking cessation (3 weeks) and
nicotine patch supplementation, (4) the effect of aspirin
consumption, and (5) the effects of 5 days' dosing with vitamin E (100
and 800 U), vitamin C (2 g), and their combination.
8-epi-PGF2 excretion (in
pmol/mmol, mean±SEM) was 176.5±30.6 in heavy smokers, 92.7±4.8
(P<.05) in moderate smokers, and 54.1±2.7
(P<.005) in nonsmokers. Urinary levels fell from
145.5±24.9 to 114.6±27.1 (week 2, P<.05) and 112.6±24.9
(week 3, P<.05) on cessation of smoking. Aspirin treatment
failed to suppress urinary levels of
8-epi-PGF2 despite a significant
reduction in urinary 11-dehydro-TxB2 production and
suppression of 8-epi-PGF2 and
TxB2 in serum. Vitamin C (pre, 194.6±40.9; post,
137.2±34.1; P<.05) and a combination of vitamin C and E
(pre, 171.0±39.8; post, 133.5±29.6; P<.05) suppressed
urinary 8-epi-PGF2,
whereas vitamin E alone had no effect.
Conclusions Urinary
8-epi-PGF2 may represent
a noninvasive, quantitative index of oxidant stress in vivo. Elevated
levels of 8-epi-PGF2 in smokers
may be modulated by quitting cigarettes and switching to nicotine
patches or by antioxidant vitamin therapy.
Key Words: smoking • prostaglandins • free radicals • isoprostanes • 8-epi-PGF2
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Cigarette smoking exacts a continuing toll on the public health. Deaths caused by cardiovascular disease attributed to cigarette smoking in the United States are estimated at more than 150 000 annually.1 2 Among the mechanisms hypothesized to contribute to smoking-induced vascular damage is oxidant injury.3 4 5 Highly reactive elements in cigarette smoke facilitate DNA adduct formation6 7 and may directly induce platelet activation and vascular dysfunction.8 9
A detailed understanding of oxidant injury in vivo has been precluded by the lack of reliable indexes of this process that are biochemically stable and susceptible to accurate quantification in a noninvasive manner.10 11 Traditionally, the susceptibility of lipoproteins to oxidation ex vivo,12 the detection of chemical adducts ex vivo,13 and reliance on nonspecific or intermediate indexes of the process, such as measurement of malondialdehyde14 or conjugated dienes,15 have been used in clinical studies.
Recently, attention has focused on families of free
radical–catalyzed isomers of arachidonic acid, the
isoprostanes (Fig 1
), as stable products of lipid
peroxidation that circulate in human plasma and are excreted in
urine.16 17 Using an estimate of F2
isoprostanes based on a PGF2 internal
standard, Morrow and colleagues have reported increased levels in
cigarette smokers.18 The present study confirms and
extends these findings.
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We have developed a method to measure specifically
8-epi-PGF2, an abundant
F2 isoprostane with mitogenic19
and vasoconstrictor17 capability. Excretion is
dose-dependently increased in apparently healthy chronic cigarette
smokers and falls when they switch to nicotine patches. Although
8-epi-PGF2 may be formed in
either a free radical– or a COX-dependent manner,20 the
increment in smokers in vivo is suppressed by antioxidant vitamins but
not by aspirin. This contrasts with the smoking-related increment
in thromboxane metabolite formation, reflective of
platelet activation, which is suppressed by aspirin.
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Methods |
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Clinical Trial Design
The clinical studies were performed at the Center for Cardiovascular Science at the Mater Hospital, a teaching hospital of University College in Dublin, Ireland. Informed consent was obtained from all subjects. Both nonsmoking and smoking volunteers were apparently healthy, with normal physical examination, biochemical screen, and full blood count. They reflected the ethnic catchment area of the hospital; all were white. The smokers ranged in age from 20 to 47 years (median, 27 years). No smokers or control subjects were taking any medications, including vitamins.
Five studies were performed. The first, a cross-sectional investigation, involved the collection of spot free-flow urine samples between 9 and 11 AM in 24 chronic cigarette smokers (18 men) who had smoked at least 15 cigarettes per day for the preceding 2 weeks. Corresponding samples were collected in 24 age- and sex-matched control subjects. All subsequent studies were carried out in volunteers from this first study. Their daily intake of cigarettes ranged from 15 to 45 (median, 25), and they had 4 to 40 pack-years of smoking (median, 15 years). The frequency of cigarette smoking was assessed by diary records and interview. Urinary cotinine, a stable metabolite of nicotine, was measured in urine samples as an index of nicotine consumption in volunteers. During these studies they smoked a single brand of cigarettes containing 1.2 mg nicotine and 12 mg tar.
The second study was a formal assessment of the dose-response
relationship between the number of cigarettes smoked and urinary
8-epi-PGF2. Chronic
smokers were brought to steady state by smoking either 15 to 30
cigarettes (median, 23) per day (moderate smokers; n=5) or >30
cigarettes per day (heavy smokers; n=5; range of number of cigarettes,
31 to 45; median, 38) for at least 7 days before collection of three
successive 24-hour urine collections for measurement of
8-epi-PGF2, cotinine, and
creatinine. The coefficient of variation of urinary
8-epi-PGF2 for triplicate 24-hour
samples in the 10 volunteers ranged from 0.5% to 15% (median, 2%).
Samples were collected in age- and sex-matched nonsmoking
volunteers. In 8 nonsmoking volunteers, the coefficient of variation
for four 12-hour urine samples over a 2-week period ranged from 3% to
19% (median, 10%).
The third study was designed to assess the effects of smoking cessation
on urinary 8-epi-PGF2 in the
cigarette smokers. Six male chronic smokers (age range, 20 to 47 years;
median, 32 years) who had smoked >30 cigarettes per day for at least 2
weeks (range, 2 weeks to 10 years) performed two 24-hour collections
for 8-epi-PGF2,
creatinine, and cotinine just before quitting. They were
placed on nicotine patches (Nicotinell, 21 mg/d; Ciba Geigy
Pharmaceuticals) on completion of the collection and were maintained on
them while urine was collected for analyses on days 13, 14, 20,
and 21 after quitting.
We have previously described the increment in urinary
thromboxane metabolites observed in apparently healthy
cigarette smokers.21 This is reflective of platelet
activation.21 22 Prompted by this observation and the
knowledge that 8-epi-PGF2,
unlike other F2 isoprostanes, may be formed by
COX,20 we assessed the effects of aspirin on urinary
8-epi-PGF2 and
11-dehydro-TxB2 in chronic cigarette smokers. Groups of
moderate (n=5) and heavy (n=4) smokers collected 24-hour urine samples
for analysis of 11-dehydro-TxB2 and
8-epi-PGF2 before (two
collections) and after (two collections) dosing with aspirin 75 mg/d
for 10 days. TxB2 and
8-epi-PGF2 were measured in serum
samples obtained at the initiation of these urine collections. Healthy,
nonsmoking control subjects (n=6) were randomized to receive either
aspirin 325 mg as a single oral dose or a matching placebo. Urine
(12-hour collections) and serum (at initiation of the urine
collections) were collected before dosing and commencing 12 hours after
drug administration.
Finally, the effects of short-term therapy with vitamins E and C
were assessed in the smokers. Initially, five moderate smokers
collected 24-hour urine samples for
8-epi-PGF2 3 days before and 2
days after receiving vitamin E (Roche Pharmaceuticals; 100 U/d for 5
days). Subsequently, a group of heavy smokers were allocated to receive
(1) vitamin E 400 U twice per day (n=7), (2) vitamin C (Roche
Pharmaceuticals) 1 g twice per day (n=5), and (3) a combination of the
two vitamins at these doses (n=4). Urine (24-hour sample) and serum
were collected before (two collections) and at the end of (two
collections) the 5-day dosing periods. A 2-week washout intervened
between treatments.
Biochemical Analysis
Urinary
8-epi-PGF220 23 and
11-dehydro-TxB224 and serum
TxB225 were measured by GC/MS as we have
previously described. Values were expressed as picomoles per millimole
of creatinine (urine) or picomoles per milliliter (serum).
Urinary cotinine was measured by radioimmunoassay,26 and
levels were expressed as nanomoles per millimole of
creatinine.
Statistical Analysis
Sample size calculations were based on the desire to detect a
difference of at least 50% with =.05 and a power (1-ß)=.9.
An unpaired t test was used when two samples were being
compared. More than two samples were compared by a one-way ANOVA
and, if significant differences occurred, by Duncan multiple range
tests to assess where the difference lay. The within-cell median
was used as a response variable for smoking cessation data and
vitamin data and analyzed as a one-way ANOVA with repeated
measures by use of a general linear model. All data are expressed as
mean±SEM, and differences were considered significant at a value of
P<.05.
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Results |
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Urinary 8-epi-PGF2
excretion
was significantly increased in the cross-sectional study (Fig 2) in the chronic smokers (122.5±10.8 [mean±SEM]
pmol/mmol creatinine) compared with the age- and
sex-matched nonsmoking control subjects (63.7±5.0 pmol/mmol
creatinine; P<.005).
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A dose-response relationship was observed between the number of
cigarettes smoked and both urinary cotinine and urinary
8-epi-PGF2 (Fig 3). Heavy smokers had an average excretion of
8-epi-PGF2 of 176.5±30.6
pmol/mmol creatinine compared with 92.7±4.8 pmol/mmol
creatinine in moderate smokers (P<.05) and
54.1±2.7 pmol/mmol creatinine in matched nonsmoking
control subjects (P<.005). Smoking was a significant
variable (F=28.4; P<.0001) in
8-epi-PGF2 excretion.
Furthermore, pairwise comparison indicated a significant difference
between the moderate smokers and both the nonsmoking and
heavy-smoking groups. Urinary cotinine levels were 2199±376
nmol/mmol creatinine in heavy smokers compared with 630±33
nmol/mmol creatinine in moderate smokers
(P<.05) and 32±3.2 nmol/mmol creatinine in
nonsmokers (P<.005). The Pearson correlation coefficient
for urinary values of 8-epi-PGF2
and cotinine in all smokers was .46 (P=.09) (Fig 4). Thus, a tendency for
8-epi-PGF2 to correlate with
urinary cotinine failed to attain conventional statistical
significance.
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Urinary 8-epi-PGF2 fell
significantly on cessation of smoking in the heavy smokers (Fig 5A). Although the data exhibited
heterogeneity, the levels fell from a precessation mean
of 145.5±24.9 pmol/mmol creatinine to 114.6±27.1
(P<.05) at 2 weeks and remained suppressed at 112.6±24.9
(P<.05) 3 weeks after quitting. Smoking was a significant
variable in urinary cotinine excretion (F=14.6;
P<.0001); levels, as expected, fell after quitting (Fig 5B)
and remained at a plateau level consistent with nicotine patch
supplementation (precessation mean, 2312±751 nmol/mmol
creatinine; week 1, 982±334; week 2, 928±340; week 3,
871±334).
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Inhibition of COX by aspirin treatment significantly suppressed
thromboxane biosynthesis in vivo, as reflected by urinary
excretion of 11-dehydro-TxB2, in all groups tested
(Fig 6A). Levels (in pmol/mmol creatinine,
mean±SEM) fell from 158.4±14.4 to 39.3±10.4 in nonsmokers
(P<.005), 200.8±21.5 to 70.0±9.2 in moderate smokers
(P<.005), and 419.6±21.8 to 105.9±9.8 in heavy
smokers (P<.005). Smoking was a significant variable in
urinary 11-dehydro-TxB2 excretion before aspirin
administration (F=46.3; P<.0001), and pairwise
analysis revealed a significant difference between heavy
smokers and both moderate smokers and nonsmokers. Concomitantly,
aspirin reduced ex vivo serum TxB2 production by
>97% in all groups (Fig 7). Urinary
8-epi-PGF2, by contrast,
was uninfluenced by aspirin administration even in heavy smokers who
had significantly raised levels (P<.05) (Fig 6B). However,
aspirin did suppress serum
8-epi-PGF2 by roughly 80% ex
vivo in moderate and heavy smokers (Fig 7). Urinary cotinine levels
were similar before and after aspirin administration.
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Vitamin E (100 U [moderate smokers] or 800 U [heavy smokers] per
day) failed to suppress urinary
8-epi-PGF2 excretion
(Table). Vitamin C, by contrast, administered at 2 g/d,
significantly depressed urinary
8-epi-PGF2 alone and in
combination with vitamin E (800 U/d).
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Discussion |
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Isoprostanes belong to a family of free radical–catalyzed products of arachidonic acid.16 27 28 F2 isoprostanes are formed in response to oxidant stress, initially in situ, via the formation of peroxyl radicals of arachidonic acid in the phospholipid29 (Fig 1
). Subsequent cleavage and release into plasma appear to result
from the action of a phospholipase A2. One of the more
abundant F2 isoprostanes,
8-epi-PGF2, exhibits
biological activity. It is a vasoconstrictor in the renal and
pulmonary vasculature and a mitogen in vascular smooth muscle
cells.17 19 30 Although these effects are blocked by
antagonists of the thromboxane receptor,
8-epi-PGF2 differs from
thromboxane analogues in its effects on platelets, in which
it induces a shape change response but not irreversible
aggregation.31 32
Given its potential as both an endogenous ligand for the
thromboxane receptor and a marker of oxidant stress in
vivo, we developed a specific and sensitive assay for
8-epi-PGF2.20
Previously, biosynthesis of F2 isoprostanes has been
estimated with an internal standard for the COX product of
arachidonic acid,
PGF2.16 Using this
latter approach, Morrow and colleagues18 recently reported
increased formation of these compounds in cigarette smokers. We
performed a series of studies that extend these observations and
support the utility of the specific measurement of
8-epi-PGF2 as an index of free
radical generation in vivo.
First, urinary 8-epi-PGF2 is
elevated in apparently healthy cigarette smokers compared with age- and
sex-matched control subjects. Furthermore, this distinction was
apparent whether the comparison was based on "spot" urine
collections or on aliquots of varied duration (12 or 24 hours).
Together with the availability of a GC/MS-validated immunoassay for
this compound,33 this observation greatly enhances the
potential utility of this approach to the study of oxidant stress in
vivo.
Second, there was a relationship between the number of cigarettes
smoked and 8-epi-PGF2 excretion.
Thus, urinary 8-epi-PGF2 was
higher in individuals smoking more than 30 cigarettes per day than in
those smoking 15 to 30 cigarettes per day. Urinary cotinine was also
higher in the heavy smokers and tended to correlate with urinary
8-epi-PGF2. However, this
particular relationship did not attain conventional statistical
significance (r=.46; P=.09). This is
unsurprising, because the effects of nicotine, of which cotinine is a
urinary metabolite,34 on
8-epi-PGF2 may be quite distinct
from those of cigarette smoking. Indeed, the precise constituents of
cigarette smoke that contribute to
8-epi-PGF2 excretion in smokers
are unclear. Cigarette tar contains stable semiquinone free radicals,
which, in aqueous solutions such as pulmonary fluid and plasma,
are capable of reducing oxygen to superoxide, with subsequent
dismutation to hydrogen peroxide.35 36 Metal ions in
cigarette tar and body fluids can catalyze the formation of the
hydroxyl radical from hydrogen peroxide via the Fenton reaction.
Furthermore, the gas phase of cigarette smoke contains highly unstable
organic radicals that are maintained in smoke for prolonged periods
(>10 minutes). Nitric oxide and isoprene play a central role in this
self-sustaining process by producing alkoxyl and peroxyl
radicals.36 37 These, in turn, may react with superoxide
in aqueous solutions to form peroxynitrite.
Finally, the degree to which free radicals might generate isoprostanes
directly or via activation of monocytes, macrophages, and
platelets, which, in turn, themselves generate free radicals,
remains to be established. Thus, although both urinary cotinine and
8-epi-PGF2 fell when the heavy
smokers were switched to nicotine patches, this is consistent
with both indexes reflecting consequences of cigarette smoking, rather
than necessarily implying a causal relationship between them.
Interestingly, on smoking cessation, urinary
8-epi-PGF2 failed to decline to
levels observed in nonsmokers. This implies that abstention from
smoking for 3 weeks reduces but does not abolish the oxidant stress
associated with chronic, heavy cigarette smoking. Alternatively, it is
possible that the ex-smokers were exposed to significant passive
smoking in their homes or social environment. Indeed, a number of
smokers did come from smoking households. However, the effect of such
environmental influences on baseline
8-epi-PGF2 excretion was not
assessed formally.
8-epi-PGF2 differs from other
F2 isoprostanes in that biological activity has been
ascribed to it, as mentioned previously. It is unclear whether it might
act as an incidental ligand at the thromboxane
receptor,38 activate a related but distinct
receptor,19 or exhibit no autacoidal activity in vivo.
8-epi-PGF2 does not
activate the recombinant PGF2
receptor in in vitro expression systems (A. Ford-Hutchinson, PhD,
personal communication, 1994). Intuitively, it would be surprising if a
product of lipid oxidation might have its own receptor. However, we
have observed recently that
8-epi-PGF2, as distinct
from other F2 isoprostanes, can be formed in small amounts
by the COX-1 enzyme in activated human
platelets20 (Fig 1). Thus, it is important to
determine the extent to which an increment in urinary
8-epi-PGF2 in cigarette smokers
reflects free radical–catalyzed or COX-dependent formation of the
compound in vivo. This is particularly true in the case of cigarette
smoking, in which we have previously described elevated excretion
of thromboxane metabolites, reflective of both platelet
activation and increased COX turnover.21 22
Inhibition of platelet COX-1 by aspirin
consumption39 40 completely suppressed serum
TxB2 in the smokers ex vivo. Serum concentrations of
8-epi-PGF2, which are
considerably lower than those of TxB2 (733±220 pmol/L
versus 513±70 nmol/L), are also suppressed by aspirin consumption by
the smokers, but to a lesser extent than was the case with
TxB2 (mean, 82% versus mean, 98%). Serum
8-epi-PGF2 levels were similar in
moderate and heavy smokers at baseline (data not shown). This is not
surprising, since there is precedence for equivalent serum levels
despite significant differences in urinary production of
TxB2 in nonsmokers, moderate smokers, and heavy
smokers.21 Thus, it appears that both a COX-dependent and
a COX-independent component of
8-epi-PGF2 generation are
present in human serum. However, measurement of
8-epi-PGF2 in serum samples
heated to 37°C for 1 hour25 is probably reflective of
the capacity for product formation in serum rather than actual
biosynthesis. Thus, serum concentrations of TxB2 exceed
estimated endogenous plasma concentrations by roughly
2000-fold.41
Measurement of urinary 11-dehydro-TxB2 is a validated
index of thromboxane synthesis in vivo.25 42
We confirmed our previous observations21 of a
dose-related increase in excretion of 11-dehydro-TxB2
in apparently healthy cigarette smokers in the present study.
However, while aspirin administration suppressed urinary
11-dehydro-TxB2, excretion of
8-epi-PGF2 was unaltered. These
results suggest that although the COX-dependent pathway may be a
significant contributor to serum
8-epi-PGF2 production ex
vivo, it remains a trivial component of overall
8-epi-PGF2 biosynthesis, as
reflected by urinary production. This holds true even in the
setting of moderate COX activation, such as occurs in heavy cigarette
smokers. Whether this holds true in settings of more marked
platelet or neutrophil activation remains to be addressed.
Similarly, although studies of the disposition of
8-epi-PGF2 are under way, it is
probable that, like that of urinary prostaglandin
metabolites, its utility will be as a noninvasive time-integrated
index of total body biosynthesis of this isoprostane. The relative
tissue contribution to urinary levels would be expected to vary as a
function of the disease under study.43
The availability of a quantitative index of oxidant stress in vivo would permit investigation of the dose-response relationship of antioxidant drugs in vivo and their rational evaluation in relevant models of disease. For example, vitamins E and C exhibit antioxidant properties at concentrations used in vitro,44 45 but little information is available as to the antioxidant properties in vivo of minimal daily allowances, of doses used in pharmacological supplementation studies, or of the wide range of intakes incidental to consumption of unrestricted diets. It is perhaps unsurprising that attempts to define benefit derived in vivo from these and other antioxidant strategies have been frustrating, whether they involved interventional studies46 47 or population-based approaches.48 49 50
We used the chronic cigarette smokers to evaluate the consequences of
short-term administration of two antioxidant vitamins on urinary
8-epi-PGF2. In contrast to
the effects of aspirin, administration of vitamin C, 2 g/d for 5 days,
resulted in a significant decline of
8-epi-PGF2 by an average 29%. A
similar significant depression of
8-epi-PGF2 excretion (mean, 23%)
was observed when the smokers were treated with vitamin E 800 U/d in
combination with vitamin C. Interestingly, vitamin E alone, at either
100 U/d (in moderate smokers) or 800 U/d (in heavy smokers), failed to
suppress 8-epi-PGF2 excretion
significantly. The apparent efficacy of vitamin C is not surprising,
given the depleted levels of this vitamin that have been demonstrated
in chronic smokers.51 Furthermore, vitamin C has been
shown to be superior to vitamin E in protecting plasma lipids and LDL
from oxidative stress.45 52 This appears to be
particularly important in plasma exposed to the gas phase of cigarette
smoke, since lipid peroxidation is initiated only after vitamin C has
been consumed.45 Despite the inability of the hydrophobic
vitamin C to suppress oxidation in lipophilic membranes, it recycles
vitamin E within the lipid membrane, prolonging its antioxidant
effect.53 Thus, the relative deficiency of vitamin C in
cigarette smokers may limit the antioxidant efficacy of vitamin E
administered alone. Indeed, an increased rate of HDL oxidation has been
reported in cigarette smokers who received supplemental vitamin E
compared with reduced HDL oxidation in smokers administered a
combination of vitamin E and vitamin C.54 These
observations illustrate the potential utility of
8-epi-PGF2 in antioxidant
dose-finding and have prompted the initiation of a more detailed
investigation of the interaction of dose and duration of therapy with
antioxidant vitamins on
8-epi-PGF2 excretion.
Our results are consistent with the observations of two other
groups. Those investigators used a measurement of either F2
isoprostanes or 8-oxo-7,8-dihydro-2-deoxyguanosine, the latter thought
to reflect repair of DNA and its precursors after free radical
attack.18 55 Collectively, these results suggest that
coincident with but distinct from platelet activation, apparently
healthy individuals who smoke cigarettes exhibit abnormal levels of
oxidant stress in vivo. The present study is also
consistent with our finding of elevated urinary
8-epi-PGF2 in other conditions
putatively associated with oxidant stress, including reperfusion
injury, adult respiratory distress syndrome, and poisoning with
acetaminophen and paraquat.56 Elevated
8-epi-PGF2 in chronic smokers may
be reduced by quitting smoking and switching to nicotine patches or by
antioxidant vitamin therapy.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by a Program Grant from the Wellcome Trust (Dr FitzGerald) and research fellowships from the Health Research Board of Ireland (Dr Reilly), the Wellcome Trust (Dr Delanty), and the Irish Heart Foundation (Dr Reilly and Dr Delanty). Dr FitzGerald is the Robinette Foundation Professor of Cardiovascular Medicine. We are indebted to Peader McGinn, PhD, for his technical assistance, Andy Cucchiara, PhD, for advice on statistical analysis of the data, and Emer Smyth, PhD, for assistance in preparation of the manuscript.
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Footnotes |
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Reprint requests to Dr G.A. FitzGerald, Center for Experimental Therapeutics, 905 Stellar Chance Building, University of Pennsylvania, Philadelphia, PA 19104.
Received April 25, 1995; revision received December 28, 1995; accepted January 2, 1996.
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S. A. Dillon, G. M. Lowe, D. Billington, and K. Rahman Dietary Supplementation with Aged Garlic Extract Reduces Plasma and Urine Concentrations of 8-Iso-Prostaglandin F2{alpha} in Smoking and Nonsmoking Men and Women J. Nutr., February 1, 2002; 132(2): 168 - 171. [Abstract] [Full Text] [PDF]
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M. Dietrich, G. Block, M. Hudes, J. D. Morrow, E. P. Norkus, M. G. Traber, C. E. Cross, and L. Packer Antioxidant Supplementation Decreases Lipid Peroxidation Biomarker F2-isoprostanes in Plasma of Smokers Cancer Epidemiol. Biomarkers Prev., January 1, 2002; 11(1): 7 - 13. [Abstract] [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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N. N. Chan, H. M. Colhoun, and P. Vallance Cardiovascular risk factors as determinants of endothelium-dependent and endothelium-independent vascular reactivity in the general population J. Am. Coll. Cardiol., December 1, 2001; 38(7): 1814 - 1820. [Abstract] [Full Text] [PDF]
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S. Mak and G. E. Newton The Oxidative Stress Hypothesis of Congestive Heart Failure : Radical Thoughts Chest, December 1, 2001; 120(6): 2035 - 2046. [Abstract] [Full Text] [PDF]
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T. Cyrus, L. X. Tang, J. Rokach, G. A. FitzGerald, and D. Pratico Lipid Peroxidation and Platelet Activation in Murine Atherosclerosis Circulation, October 16, 2001; 104(16): 1940 - 1945. [Abstract] [Full Text] [PDF]
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G. Davi, G. Di Minno, A. Coppola, G. Andria, A. M. Cerbone, P. Madonna, A. Tufano, A. Falco, P. Marchesani, G. Ciabattoni, et al. Oxidative Stress and Platelet Activation in Homozygous Homocystinuria Circulation, September 4, 2001; 104(10): 1124 - 1128. [Abstract] [Full Text] [PDF]
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M. Trevisan, R. Browne, M. Ram, P. Muti, J. Freudenheim, A. M. Carosella, and D. Armstrong Correlates of Markers of Oxidative Status in the General Population Am. J. Epidemiol., August 15, 2001; 154(4): 348 - 356. [Abstract] [Full Text] [PDF]
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X. L. Wang, D. L. Rainwater, J. F. VandeBerg, B. D. Mitchell, and M. C. Mahaney Genetic Contributions to Plasma Total Antioxidant Activity Arterioscler Thromb Vasc Biol, July 1, 2001; 21(7): 1190 - 1195. [Abstract] [Full Text] [PDF]
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U. Palaniappan, L. J. Starkey, J. O'Loughlin, and K. Gray-Donald Fruit and Vegetable Consumption Is Lower and Saturated Fat Intake Is Higher among Canadians Reporting Smoking J. Nutr., July 1, 2001; 131(7): 1952 - 1958. [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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 L. J. Janssen Isoprostanes: an overview and putative roles in pulmonary pathophysiology Am J Physiol Lung Cell Mol Physiol, June 1, 2001; 280(6): L1067 - L1082. [Abstract] [Full Text] [PDF]
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 S Basu, M Whiteman, D L Mattey, and B Halliwell Raised levels of F2-isoprostanes and prostaglandin F2{alpha} in different rheumatic diseases Ann Rheum Dis, June 1, 2001; 60(6): 627 - 631. [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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E. P. Brass, W. R. Hiatt, A. W. Gardner, and C. L. Hoppel Decreased NADH dehydrogenase and ubiquinol-cytochrome c oxidoreductase in peripheral arterial disease Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H603 - H609. [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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 H. Hioki, N. Aoki, K. Kawano, M. Homori, Y. Hasumura, T. Yasumura, A. Maki, H. Yoshino, A. Yanagisawa, and K. Ishikawa Acute effects of cigarette smoking on platelet-dependent thrombin generation Eur. Heart J., January 1, 2001; 22(1): 56 - 61. [Abstract] [PDF]
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L. Iuliano, D. Pratico, C. Greco, E. Mangieri, G. Scibilia, G. A. FitzGerald, and F. Violi Angioplasty increases coronary sinus F2-isoprostane formation: evidence for in vivo oxidative stress during PTCA J. Am. Coll. Cardiol., January 1, 2001; 37(1): 76 - 80. [Abstract] [Full Text] [PDF]
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 B. Pignatelli, C.-Q. Li, P. Boffetta, Q. Chen, W. Ahrens, F. Nyberg, A. Mukeria, I. Bruske-Hohlfeld, C. Fortes, V. Constantinescu, et al. Nitrated and Oxidized Plasma Proteins in Smokers and Lung Cancer Patients Cancer Res., January 1, 2001; 61(2): 778 - 784. [Abstract] [Full Text]
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 L. J. Janssen, M. Premji, S. Netherton, A. Catalli, G. Cox, S. Keshavjee, and D. J. Crankshaw Excitatory and Inhibitory Actions of Isoprostanes in Human and Canine Airway Smooth Muscle J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 506 - 511. [Abstract] [Full Text]
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E. Porkkala-Sarataho, J. T. Salonen, K. Nyyssonen, J. Kaikkonen, R. Salonen, U. Ristonmaa, U. Diczfalusy, R. Brigelius-Flohe, S. Loft, and H. E. Poulsen Long-Term Effects of Vitamin E, Vitamin C, and Combined Supplementation on Urinary 7-Hydro-8-Oxo-2'-Deoxyguanosine, Serum Cholesterol Oxidation Products, and Oxidation Resistance of Lipids in Nondepleted Men Arterioscler Thromb Vasc Biol, September 1, 2000; 20(9): 2087 - 2093. [Abstract] [Full Text] [PDF]
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F. Cipollone, G. Ciabattoni, P. Patrignani, M. Pasquale, D. Di Gregorio, T. Bucciarelli, G. Davi, F. Cuccurullo, and C. Patrono Oxidant Stress and Aspirin-Insensitive Thromboxane Biosynthesis in Severe Unstable Angina Circulation, August 29, 2000; 102(9): 1007 - 1013. [Abstract] [Full Text] [PDF]
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B. Halliwell Lipid peroxidation, antioxidants and cardiovascular disease: how should we move forward? Cardiovasc Res, August 18, 2000; 47(3): 410 - 418. [Full Text] [PDF]
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A. Mezzetti, F. Cipollone, and F. Cuccurullo Oxidative stress and cardiovascular complications in diabetes: isoprostanes as new markers on an old paradigm Cardiovasc Res, August 18, 2000; 47(3): 475 - 488. [Abstract] [Full Text] [PDF]
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P. Patrignani, M. R. Panara, S. Tacconelli, F. Seta, T. Bucciarelli, G. Ciabattoni, P. Alessandrini, A. Mezzetti, G. Santini, M. G. Sciulli, et al. Effects of Vitamin E Supplementation on F2-Isoprostane and Thromboxane Biosynthesis in Healthy Cigarette Smokers Circulation, August 1, 2000; 102(5): 539 - 545. [Abstract] [Full Text] [PDF]
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B. Frey, R. Haupt, S. Alms, G. Holzmann, T. König, H. Kern, W. Kox, B. Rüstow, and M. Schlame Increase in fragmented phosphatidylcholine in blood plasma by oxidative stress J. Lipid Res., July 1, 2000; 41(7): 1145 - 1153. [Abstract] [Full Text]
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R. A Riemersma, K. F Carruthers, R. A Elton, and K. A. Fox Vitamin C and the risk of acute myocardial infarction Am. J. Clinical Nutrition, May 1, 2000; 71(5): 1181 - 1186. [Abstract] [Full Text] [PDF]
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O. T. Raitakari, M. R. Adams, R. J. McCredie, K. A. Griffiths, R. Stocker, and D. S. Celermajer Oral vitamin C and endothelial function in smokers: short-term improvement, but no sustained beneficial effect J. Am. Coll. Cardiol., May 1, 2000; 35(6): 1616 - 1621. [Abstract] [Full Text] [PDF]
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T. Heitzer, C. Brockhoff, B. Mayer, A. Warnholtz, H. Mollnau, S. Henne, T. Meinertz, and T. Munzel Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers : Evidence for a Dysfunctional Nitric Oxide Synthase Circ. Res., February 4, 2000; 86 (2): e36 - e41. [Abstract] [Full Text] [PDF]
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T. Neunteufl, U. Priglinger, S. Heher, M. Zehetgruber, G. Soregi, S. Lehr, K. Huber, G. Maurer, F. Weidinger, and K. Kostner Effects of vitamin E on chronic and acute endothelial dysfunction in smokers J. Am. Coll. Cardiol., February 1, 2000; 35(2): 277 - 283. [Abstract] [Full Text] [PDF]
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A. Burke, J. A. Lawson, E. A. Meagher, J. Rokach, and G. A. FitzGerald Specific Analysis in Plasma and Urine of 2,3-Dinor-5,6-dihydro-isoprostane F2alpha -III, a Metabolite of Isoprostane F2alpha -III and an Oxidation Product of gamma -Linolenic Acid J. Biol. Chem., January 28, 2000; 275(4): 2499 - 2504. [Abstract] [Full Text] [PDF]
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E. Södergren, J. Cederberg, S. Basu, and B. Vessby Vitamin E Supplementation Decreases Basal Levels of F2-Isoprostanes and Prostaglandin F2{alpha} in Rats J. Nutr., January 1, 2000; 130(1): 10 - 14. [Abstract] [Full Text]
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 H. Li, J. A. Lawson, M. Reilly, M. Adiyaman, S.-W. Hwang, J. Rokach, and G. A. FitzGerald Quantitative high performance liquid chromatography/tandem mass spectrometric analysis of the four classes of F2-isoprostanes in human urine PNAS, November 9, 1999; 96(23): 13381 - 13386. [Abstract] [Full Text] [PDF]
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J. A. Lawson, J. Rokach, and G. A. FitzGerald Isoprostanes: Formation, Analysis and Use As Indices of Lipid Peroxidation in Vivo J. Biol. Chem., August 27, 1999; 274(35): 24441 - 24444. [Full Text] [PDF]
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M. Reza Mehrabi, C. Ekmekcioglu, F. Tatzber, A. Oguogho, R. Ullrich, A. Morgan, F. Tamaddon, M. Grimm, H. D Glogar, and H. Sinzinger The isoprostane, 8-epi-PGF2{alpha}, is accumulated in coronary arteries isolated from patients with coronary heart disease Cardiovasc Res, August 1, 1999; 43(2): 492 - 499. [Abstract] [Full Text] [PDF]
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R. BRIGELIUS-FLOHÉ and M. G. TRABER Vitamin E: function and metabolism FASEB J, July 1, 1999; 13(10): 1145 - 1155. [Abstract] [Full Text]
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A. C Carr and B. Frei Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans Am. J. Clinical Nutrition, June 1, 1999; 69(6): 1086 - 1107. [Abstract] [Full Text] [PDF]
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A. CARR and B. FREI Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J, June 1, 1999; 13(9): 1007 - 1024. [Abstract] [Full Text]
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 D. Pratico, D. Ferro, L. Iuliano, J. Rokach, F. Conti, G. Valesini, G. A. FitzGerald, and F. Violi Ongoing Prothrombotic State in Patients With Antiphospholipid Antibodies: A Role for Increased Lipid Peroxidation Blood, May 15, 1999; 93(10): 3401 - 3407. [Abstract] [Full Text] [PDF]
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R. Wever, P. Boer, M. Hijmering, E. Stroes, M. Verhaar, J. Kastelein, K. Versluis, F. Lagerwerf, H. van Rijn, H. Koomans, et al. Nitric Oxide Production Is Reduced in Patients With Chronic Renal Failure Arterioscler Thromb Vasc Biol, May 1, 1999; 19(5): 1168 - 1172. [Abstract] [Full Text] [PDF]
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D. Ferro, S. Basili, D. Pratico, L. Iuliano, G. A. FitzGerald, and F. Violi Vitamin E Reduces Monocyte Tissue Factor Expression in Cirrhotic Patients Blood, May 1, 1999; 93(9): 2945 - 2950. [Abstract] [Full Text] [PDF]
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T. Heitzer, S. Y. Herttuala, E. Wild, J. Luoma, and H. Drexler Effect of vitamin E on endothelial vasodilator function in patients with hypercholesterolemia, chronic smoking or both J. Am. Coll. Cardiol., February 1, 1999; 33(2): 499 - 505. [Abstract] [Full Text] [PDF]
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G. Davi, G. Ciabattoni, A. Consoli, A. Mezzetti, A. Falco, S. Santarone, E. Pennese, E. Vitacolonna, T. Bucciarelli, F. Costantini, et al. In Vivo Formation of 8-Iso-Prostaglandin F2{alpha} and Platelet Activation in Diabetes Mellitus : Effects of Improved Metabolic Control and Vitamin E Supplementation Circulation, January 19, 1999; 99(2): 224 - 229. [Abstract] [Full Text] [PDF]
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C. Chiabrando, A. Valagussa, C. Rivalta, T. Durand, A. Guy, E. Zuccato, P. Villa, J.-C. Rossi, and R. Fanelli Identification and Measurement of Endogenous beta -Oxidation Metabolites of 8-epi-Prostaglandin F2alpha J. Biol. Chem., January 15, 1999; 274(3): 1313 - 1319. [Abstract] [Full Text] [PDF]
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J. L. Witztum To E or Not To E—How Do We Tell? Circulation, December 22, 1998; 98(25): 2785 - 2787. [Full Text] [PDF]
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