(Circulation. 1997;96:1097-1101.)
© 1997 American Heart Association, Inc.
Articles |
Association Between Cigarette Smoking and Lipid Peroxidation in a Controlled Feeding Study
From the Welch Center for Prevention, Epidemiology and Clinical Research, Department of Medicine (E.R.M., L.J.A.), The Johns Hopkins Medical Institutions, and the Department of Epidemiology (L.J.A.) and Department of Environmental Health Sciences (L.J., T.H.R.), Johns Hopkins School of Hygiene and Public Health, Baltimore, Md.
Correspondence to Edgar R. Miller III, MD, PhD, Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins Medical Institutions, 2024 East Monument St, Suite 2-600, Baltimore, MD 21205-2223. E-mail ermiller{at}welchlink.welch.jhu.edu
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Abstract |
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Background Cigarette smoke may promote atherogenesis by producing oxygen-derived free radicals that damage lipids. However, evidence in support of this hypothesis is inconsistent because most studies did not control for aspects of diet (antioxidants and lipid substrate) that may confound the association between smoking and measures of lipid peroxidation.
Methods and Results The relationships between cigarette smoking and two measures of lipid peroxidation, breath ethane (an in vivo assay) and thiobarbituric acid–reactive substances (TBARS, an in vitro assay), were examined in 123 adults (11% of whom were smokers) participating in a controlled feeding study. After 3 weeks of controlled feeding on a common diet (36% total fat, 14% saturated fats, 6% polyunsaturated fats, and 12% monounsaturated fats), breath and fasting serum samples were collected for measurement of ethane and TBARS, respectively. Baseline characteristics of smokers and nonsmokers were similar, including several indices related to diet and nutritional status (albumin, cholesterol, body mass index, and oxygen radical–absorbing capacity). Cigarette smokers had significantly higher breath ethane (8.88 versus 1.71 pmol/L; P<.0001) and TBARS (24.0 versus 20.7 µmol/mL; P=.008) than nonsmokers. The interval between breath collection and the time the last cigarette was smoked was significantly and inversely correlated with breath ethane. Neither measure of lipid peroxidation was associated with measures of serum cholesterol or albumin, body mass index, or serum oxygen radical–absorbing capacity.
Conclusions Cigarette smokers have higher rates of in vivo and in vitro lipid peroxidation. These results support the hypothesis that the atherogenic effects of smoking are mediated in part by free radical damage to lipids.
Key Words: smoking • atherosclerosis • lipids • antioxidants • free radicals
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Introduction |
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Cigarette smoking is a major risk factor for development of ASCVD. It has been hypothesized that free radicals in cigarette smoke damage lipids, resulting in the formation of proatherogenic oxidized particles, specifically oxidized LDL.1 Despite this appealing hypothesis, there is little direct evidence to support it using traditional measures of lipid peroxidation.
In previous observational studies that compared the susceptibility of lipids with peroxidation in smokers and nonsmokers, the relationship between smoking status and in vitro assays has been inconsistent.2 3 4 5 One explanation for the lack of positive associations is the fact that free-living smokers and nonsmokers have different dietary patterns. Specifically, the dietary intake and serum levels of antioxidants are typically lower in smokers than in nonsmokers.6 Hence, the increased susceptibility of lipids to peroxidation in smokers may reflect lower levels of serum antioxidants rather than a true deleterious effect of cigarette smoke on lipids.
To overcome this issue, we tested the hypothesis that current cigarette smoking was associated with higher rates of in vitro and in vivo lipid peroxidation in the setting of a controlled feeding study. By providing the same diet to both smokers and nonsmokers, we controlled two aspects of diet that confound the association of smoking and lipid peroxidation, namely, dietary antioxidant and fat intake.
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Methods |
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This research was conducted as an ancillary study within the DASH study, a National Heart, Lung, and Blood Institute–sponsored clinical trial designed to assess the impact of dietary patterns on blood pressure. This ancillary study was conducted at the Johns Hopkins clinical center and was designed and analyzed only by the coauthors. Details of the DASH protocol7 and of its main results have been published elsewhere.8 The protocol was approved by a local institutional review board. All participants provided written informed consent.
Participants
Study participants consisted of 123 healthy adults (aged 
22
years) who were not taking antihypertensive medication and who had a
diastolic blood pressure of 80 to 95 mm Hg and a
systolic blood pressure <160 mm Hg. Individuals with
medication-treated hypertension could enroll if they met the blood
pressure inclusion criteria after a period of supervised medication
withdrawal. Major exclusion criteria for entry into the trial were
poorly controlled diabetes,
hypercholesterolemia,
cardiovascular event within 6 months, chronic disease
that might interfere with trial participation, pregnancy or lactation,
BMI >35 kg/m2, medications that affect blood
pressure, unwillingness to stop all vitamin and mineral supplements,
unwillingness to stop antacids containing calcium or magnesium, and
consumption of >14 alcoholic drinks per week. Mass distribution of
brochures and community-based screenings were the primary recruitment
strategies. Participants were enrolled subsequently into groups; the
first group began controlled feeding in September 1994 and the fifth
and last cohort started in January 1996. There were 14 current
cigarette smokers and 107 non–cigarette smokers across all cohorts.
All current cigarette smokers reported smoking <1 pack of cigarettes
per day.
Diet
Participants ate a common diet for 3 weeks. This diet was
designed to be relatively low in fruits and vegetables, although its
macronutrient profile corresponded to average US dietary consumption.
Participants agreed to eat just the food provided to them and nothing
else. Chemical analyses of menus indicated that the diet had
the following macronutrient profile: total fat, 35.7% kcal; saturated
fat, 14.1% kcal; polyunsaturated fat, 6.2% kcal;
monounsaturated fat, 12.4% kcal; carbohydrates,
50.5% kcal; and protein, 13.8% kcal. The diet provided an average of
1.6 servings of fruits and juices per day and 2.0 servings of
vegetables per day. Caloric intake was adjusted to maintain a stable
weight during the 3-week period.
Blood Collection and Analyses
Three weeks after the start of controlled feeding, blood samples
were collected after an overnight fast. Blood was drawn from the
antecubital vein into an unheparinized tube. Serum was allowed to clot
for 15 minutes and then centrifuged at 2000g for 15
minutes at 4°C. The serum was then transferred into 2-mL polyethylene
storage containers by means of a pipette, topped with nitrogen gas, and
quickly frozen on dry ice. Serum was stored at -70°C for a period of
<4 months, a period of storage that should have no substantial impact
on measures of TBARS or ORAC; separate analyses of serum
samples stored for 5 months demonstrated that differences between
replicate measurements (prestorage and poststorage) were similar to
reported run-to-run CVs for the assays. Serum albumin was
determined spectrophotometrically with the use of a Sigma
Diagnostics albumin assay with a reported
run-to-run CV of 1.3%.
A second aliquot of blood was separated and frozen for lipid and lipoprotein analysis. Serum lipids were measured in a Hitachi 704 chemistry analyzer. HDL cholesterol was measured on the chemistry analyzer by use of the magnetic HDL method (Polymedico). The LDL cholesterol concentration was calculated by the equation LDL Cholesterol=(Total Cholesterol-HDL Cholesterol)-(Triglycerides/5). All triglyceride levels were <400 mg/dL.
Breath Collection and Ethane Gas Analysis
Breath samples were collected in a well-ventilated room from
seated participants before they ate their noon or evening meal and
after they had rested for 1 minute. Thirty to 60 seconds of breath
(
10 L) was collected from each participant by means of a one-way,
nonrebreathing Rudolf valve connected by respiratory tubing to a 22-L
gas-tight collection bag. One investigator (E.R.M.) collected all
breath specimens. A sample of room air was also collected at each
sampling period. The interval between the time of the last cigarette
smoked by the participant and the time of breath collection was
recorded. The concentration of ethane gas was determined by
capillary gas chromatography using a method described
by Arterbery et al.9 In addition, the CO2
concentration of each patient's breath was analyzed by a
Beckman LB-3 CO2 monitor (Sensor Medics) for the purpose of
standardizing the ethane values to an alveolar CO2
concentration of 40 mm Hg, a technique that has been
successfully used elsewhere.10 Breath ethane concentration
is corrected for background ethane and for efficiency of breath
collection (as determined by CO2) and calculated as
follows: (Sample Ethane-Background Ethane)x(40/Measured
CO2). All analyses were performed within 24 hours
of collection, well within the 72-hour period of sample stability
reported.9 Ethane values are reported as picomoles per
liter (pmol/L), with a reported run-to-run CV of 3.0%.
TBARS Assay
Serum lipid peroxidation of polyunsaturated fatty acids was
estimated by the TBARS assay. Determinations of TBARS were made on
freshly thawed serum by a modification of the Yagi
method11 by the Genox Corporation. The serum sample was
incubated for 1 hour at 95°C with thiobarbituric acid, after which a
TBARS-MDA adduct was measured by absorption at 530 nm. A standard curve
for absorption and MDA concentration was then determined, and the
amount of lipid peroxidation was reported as micromolar MDA
equivalents. The run-to-run CV for TBARS at Genox was 6.5%.
ORAC Assay
The ORAC assay estimates the ability of serum to resist
oxidative damage, reflecting the combined effects of all antioxidants
in the serum rather than any individual antioxidant.12 An
indicator protein sensitive to oxidative damage (ß-phycoerythrin) was
added to serum and allowed to undergo oxidation after the addition of a
water-soluble peroxyl-radical generator, 2,2'-azobis (2-amidinopropane)
dihydrochloride, at 37°C. The oxidation of the fluorescent
protein was monitored spectrofluorometrically at 540-nm excitation and
560-nm emission every 5 minutes until extinction. The presence of
antioxidants in the serum reduces the rate of decline of the
fluorescence of the protein. A water-soluble vitamin E
analogue, Trolox, was used to establish a standard curve. One ORAC unit
is equivalent to the protection provided by 1 µmol of Trolox.
This assay was performed at the Genox Corporation, which reported a
run-to-run CV of 4.4%.
Data Analyses
For variables with a normal distribution, means (±1 SD) are
presented. Because of several extreme values, breath ethane did
not have a normal distribution; hence, medians and interquartile ranges
(quartiles 1 through 3) are presented. Differences in MDA and
breath ethane between smokers and nonsmokers were examined by use of
the Wilcoxon rank sum tests. Correlations between breath ethane
and TBARS were calculated by Spearman's correlation analysis.
In all analyses, a value of P<.05 was considered
statistically significant. Characteristics of study participants at
baseline were compared by use of 
2 tests for
categorical variables (sex and ethnicity) and two-sample Student's
t tests for continuous variables.
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Results |
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As shown in Table 1
, there were no
substantial or significant differences in age, sex, percent of black
subjects, serum albumin, total cholesterol, LDL
cholesterol, HDL cholesterol,
triglycerides, or BMI between the 107 nonsmokers and 14
smokers. ORAC was not significantly different between smokers and
nonsmokers, suggesting no difference in serum antioxidant capacity
between these two groups, at least while they consumed a common
diet.
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Age, BMI, serum cholesterol, serum albumin, and
ORAC were not associated with TBARS or ethane as indicated by
Spearman's correlation analysis (Table 2) or by visual inspection of
scatterplots (not presented). There was no significant
correlation between the in vivo (ethane) and in vitro (TBARS) measures
of lipid peroxidation (r=.06; P=.49).
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TBARS measurements were significantly higher (P=.001) in men (median, 21.85; Q1-Q3, 20.20 to 24.73) than in women (median, 20.38; Q1-Q3, 18.8 to 21.92). However, there was no gender association with breath ethane (P=.10), nor was there an association between race and TBARS (P=.18) or race and ethane (P=.46). Because the ethnicity and male:female ratio were similar in smokers and nonsmokers, there were no adjustments made for race or sex.
Breath ethane was significantly higher (P<.0001) in smokers
(median, 8.88 pmol/L; Q1-Q3, 5.41 to 16.57 pmol/L) than
in nonsmokers (median, 1.71 pmol/L; Q1-Q3, 0.76 to 3.64
pmol/L) (Fig 1). In addition,
there was an apparent temporal relationship between the time from the
last cigarette smoked and measures of breath ethane (Fig 2). Breath was substantially higher in
participants whose last cigarette was within 1 hour of breath
collection than in those individuals whose last cigarette was >1 hour
before the visit.
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As displayed in Fig 3, the serum
TBARS measurement was also significantly higher (P=.008) in
smokers (median, 24.02 µmol/mL; Q1-Q3, 21.3 to 25.9
µmol/mL) than in nonsmokers (median, 20.7
µmol/mL; Q1-Q3, 19.3 to 23.0 µmol/mL).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study demonstrated that in the setting of a controlled feeding study, current cigarette smokers have higher measures of lipid peroxidation than nonsmokers. The findings were observed while participants ate a common diet that was relatively high in fat and low in fruits and vegetables. The finding of increased lipid peroxidation in smokers supports the hypothesis that smoking increases free radical–mediated oxidative damage of lipids, a putative risk factor for ASCVD.
Previous observational studies that assessed the extent of lipid peroxidation in smokers and nonsmokers have yielded inconsistent results. In cross-sectional studies that enrolled healthy volunteers,2 patients with angina,3 diabetics,13 and young survivors of myocardial infarction,5 smokers had similar levels of in vitro lipid peroxidation compared with nonsmokers. There are several studies that showed an association between smoking and oxidative damage, including one cross-sectional study that demonstrated an association between cigarette smoking and autoantibody titer to oxidized LDL cholesterol.14 Also, in two small clinical trials of smokers, Morrow et al15 and Reilly et al16 demonstrated a relationship between smoking and levels of F2 isoprostanes (a degradation product of arachidonic acid).
To a large extent, the difficulty in establishing a clear relationship between current cigarette smoking and oxidative damage lies in the limitations of most assays. Problems with specificity and repeatability are common to most assays of lipid peroxidation.17 Another problem related to comparisons of smokers and nonsmokers is the differences in dietary patterns of each group. Assays to detect lipid peroxidation are dependant on the extent of free radical activity, the amount of serum lipid substrate, and the protective effect of serum antioxidants. The later two factors are highly dependant on patterns of dietary intake.
In unselected study populations, smokers generally have diets that are poor in nutritional sources of antioxidants; hence, dietary intake and serum levels of vitamin C, beta carotene, and vitamin E have been reported to be lower in smokers than in nonsmokers.6 In studies in which higher measures of lipid peroxidation were found in smokers than in nonsmokers, smokers also had lower serum vitamin E levels, which could account for the reported difference.18 In other studies, antioxidant vitamin supplements, including vitamin C,19 vitamin E,19 20 and beta carotene,21 decreased the extent of lipid peroxidation in smokers to baseline levels of nonsmokers after only a few weeks of supplementation. In a study exclusively of smokers, a combined antioxidant supplement resulted in increased oxidative resistance to lipid peroxidation.22 Hence, the intake of antioxidants from diet or supplements may have a major influence on the in vitro susceptibility of lipids to peroxidation2 and may account for the reported differences in lipid peroxidation between smokers and nonsmokers independent of the effects of cigarette smoke. In our study of participants eating a common diet, there were no apparent differences in surrogate nutritional indices, including serum ORAC, albumin, cholesterol, and BMI, between smokers and nonsmokers. These findings suggest that the overall nutritional status of smokers and nonsmokers was similar.
Measurement of TBARS is a commonly used in vitro assay that measures MDA formed as the degradation end product of lipid peroxidation. However, the single most important determinant of in vitro TBARS in a free-living population is the P/S ratio in the serum sample,2 a ratio determined primarily by diet. The fact that the dietary habits of smokers differ from those of nonsmokers may explain in part the inconsistent results of studies that examined the relationship between smoking status and TBARS. Hence, by providing a fixed P/S ratio (0.5), the present study controlled a major determinant of serum TBARS.
Another potential confounder of the TBARS assay is the serum lipid level, which is independent of the P/S ratio. Differences in the content of serum lipids, ie, the substrate for peroxidation, between groups may greatly influence the assay.23 In the present study, serum cholesterol levels were similar in smokers and nonsmokers. Furthermore, differences in TBARS between smokers and nonsmokers persisted after normalization for either serum cholesterol or albumin (data not reported), indicating a nominal influence of these potential confounders.
One of the major limitations for the use of breath ethane as a marker
of in vivo lipid peroxidation in cigarette smokers is that ethane is a
component of cigarette smoke. High levels of ethane are present in
cigarette smoke; the estimated time for complete washout of ethane gas
from the lungs is 1 hour.24 Similar washout times were
also noted for the oxidation product of 
-6 fatty acids (breath
pentane).25 However, it is noteworthy that the median
breath ethane of smokers whose last cigarette was >1 hour before
breath collection was higher than that of nonsmokers.
The lack of a strong association between the two measures of lipid
peroxidation, ethane and TBARS, may reflect the fact that these
products are formed by different processes. Breath ethane reflects
intracellular lipid peroxidation processes, whereas TBARS is an in
vitro serum assay. Furthermore, breath ethane is highly specific for
the oxidation product of -3 fatty acids, whereas TBARS is a
product derived from all polyunsaturated fatty acids present in
the serum and lacks specificity.
In conclusion, cigarette smokers have higher rates of in vivo and in vitro lipid peroxidation. These results support the hypothesis that the atherogenic effects of smoking are mediated in part by free radical damage to lipids.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This research was supported by grants from the National Institutes of Health (HL-54906, HL-02642, ES-03156, and RR-00722), an American Heart Association–Maryland Affiliate Research Fellowship award to Dr Miller, and a grant from the US Air Force (F-49620-95-0270).
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Footnotes |
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Presented in part at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 10-13, 1996, and previously published in abstract form (Circulation. 1996;94:I-143).
Received December 19, 1996; revision received March 17, 1997; accepted March 23, 1997.
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