Increase in Circulating Products of Lipid Peroxidation (F2-Isoprostanes) in Smokers — Smoking as a Cause of Oxidative Damage
Jason D. Morrow, M.D., Balz Frei, Ph.D., Atkinson W. Longmire, M.D., J. Michael Gaziano, M.D., Sean M. Lynch, Ph.D., Yu Shyr, Ph.D., William E. Strauss, M.D., John A. Oates, M.D., and L. Jackson Roberts, M.D.
Background It has been hypothesized that the pathogenesis ofdiseases induced by cigarette smoking involves oxidative damageby free radicals. However, definitive evidence that smokingcauses the oxidative modification of target molecules in vivois lacking. We conducted a study to determine whether the productionof F2-isoprostanes, which are novel products of lipid peroxidation,is enhanced in persons who smoke.
Methods We measured the levels of free F2-isoprostanes in plasma,the levels of F2-isoprostanes esterified to plasma lipids, andthe urinary excretion of metabolites of F2-isoprostanes in 10smokers and 10 nonsmokers matched for age and sex. The short-termeffects of smoking (three cigarettes smoked over 30 minutes)and the effects of two weeks of abstinence from smoking on levelsof F2-isoprostanes in the circulation were also determined inthe smokers.
Results Plasma levels of free and esterified F2-isoprostaneswere significantly higher in the smokers (mean ±SD, 242±147and 574±217 pmol per liter, respectively) than in thenonsmokers (103±19 and 345±65 pmol per liter;P = 0.02 for free F2-isoprostanes and P = 0.03 for esterifiedF2-isoprostanes). Smoking had no short-term effects on the circulatinglevels of F2-isoprostanes. However, the levels of free and esterifiedF2-isoprostanes fell significantly after two weeks of abstinencefrom smoking (250±156 and 624±214 pmol per liter,respectively, before the cessation of smoking, as compared with156±67 and 469±108 pmol per liter after two weeks'cessation; P = 0.03 for free F2-isoprostanes and P = 0.02 foresterified F2-isoprostanes).
Conclusions The increased levels of F2-isoprostanes in the circulationof persons who smoke support the hypothesis that smoking cancause the oxidative modification of important biologic moleculesin vivo.
Cigarette smoking is a serious health problem worldwide. Smokinghas been strongly implicated as a risk factor for chronic obstructivepulmonary disease, cancer, and atherosclerosis.1,2,3 Becausecigarette smoke is known to contain a large number of oxidants,4it has been hypothesized that many of the adverse effects ofsmoking may result from oxidative damage to critical biologicsubstances. Such damage could result both from oxidants presentin cigarette smoke and from the activation of phagocytic cellsthat generate reactive oxygen species.4,5
Oxidative inactivation of antiproteases may be involved in thedevelopment of chronic obstructive pulmonary disease, and oxidativemodification of DNA can lead to the development of cancer.4,6,7It has been shown that oxidatively modified low-density lipoprotein(LDL), but not native LDL, is recognized by scavenger receptorsand taken up by macrophages, a process considered pivotal inthe development of foam cells in atherosclerotic lesions.8 Thus,oxidation of LDL by cigarette smoke may contribute to the causativelink between cigarette smoking and atherogenesis. Although previouslythere was controversy about whether direct exposure of LDL tocigarette smoke in vitro results in oxidative modification,9,10we recently demonstrated the formation of lipid hydroperoxidesafter the exposure of plasma to the gas phase of cigarette smoke.11Other evidence suggesting that smokers are subjected to oxidativestress includes the findings that they have lower levels ofthe antioxidant ascorbic acid (vitamin C) than nonsmokers andthat smokers' risk of coronary artery disease correlates inverselywith their intake of the antioxidants vitamin E and beta carotene.12,13,14,15
In spite of the circumstantial data from in vitro studies andmeasurements of antioxidant levels in smokers suggesting thatcigarette smoke may cause oxidative injury, whether this processoccurs in vivo has been controversial.10,16,17,18 The conflictingevidence can largely be attributed to the fact that most methodspreviously available to assess oxidative stress in humans havebeen inaccurate and unreliable.19
Recently, we discovered a series of bioactive prostaglandinF2–like compounds (termed F2-isoprostanes) that are producedindependently of the cyclooxygenase enzyme in humans by theperoxidation of arachidonic acid, catalyzed by free radicals(Figure 1).20 F2-isoprostanes are initially formed in situ onphospholipids and are subsequently released preformed.21 Levelsof F2-isoprostanes in normal human biologic fluids exceed thoseof cyclooxygenase-derived prostanoids by approximately one totwo orders of magnitude. In addition, levels of F2-isoprostanes— both free in the circulation and esterified to tissuephospholipids — increase dramatically in animal modelsof oxidant injury.21,22 The most widely used test of lipid peroxidationis the measurement of malondialdehyde with the thiobarbituricacid–reacting substances assay.19 We recently demonstratedthat the F2-isoprostane level is far superior to measurementsof thiobarbituric acid–reacting substances as an indexof lipid peroxidation in vivo.23 Thus, the discovery of F2-isoprostanesis considered an important advance in our ability to detectoxidant injury.
Figure 1. Mechanism of Formation and Structures of the F2-Isoprostanes.
The F2-isoprostanes are derived from arachidonic acid (top), which undergoes peroxidation catalyzed by free radicals to yield arachidonyl radical intermediates, which are then transformed to a series of prostaglandin F2–like compounds composed of four regioisomers (I through IV). Each regioisomer consists of eight racemic diastereomers. The dots outside the molecules indicate unpaired electrons. The lines of dots inside the molecules represent the delocalization of the electrical charge over several carbon atoms.Stereochemistry is not shown.
We undertook this study to assess the hypothesis that cigarettesmoking can cause oxidative modification of important biologicmolecules in humans by determining whether the production ofF2-isoprostanes is increased in persons who smoke.
Methods
Measurements of F2-Isoprostanes
Blood was drawn into Vacutainer tubes containing EDTA and immediatelycentrifuged to separate the plasma. An aliquot of plasma wasthen removed and stored at -70°C for measurement of lipid-solubleantioxidants. For ascorbic acid and uric acid measurements,the plasma was extracted with metaphosphoric acid before storageat -70°C. The remainder of the plasma was immediately processedfor the measurement of F2-isoprostanes. Levels of free F2-isoprostanesin plasma and of F2-isoprostanes esterified to plasma lipidswere measured by stable-isotope-dilution mass-spectrometricassay.24 The precision of the assay for free F2-isoprostanesis ±6 percent, and the accuracy is 96 percent. The precisionof the assay for esterified F2-isoprostanes in plasma is ±8percent. Data are expressed in picomoles per liter. We recentlyidentified tetranor dicarboxylic acid urinary metabolites ofF2-isoprostanes that contain one keto group and one double bondwith a molecular weight of 328.25 These metabolites were measuredby a mass-spectrometric method, previously described,25 thathas a precision of ±12 percent. Data are expressed inpicomoles per millimole of creatinine.
Measurements of Antioxidants in Plasma
Plasma concentrations of ascorbic acid (vitamin C), uric acid,alpha- and gamma-tocopherol (vitamin E), alpha and beta carotene,cryptoxanthin, lycopene, lutein and zeaxanthin, and retinolwere measured by high-performance liquid chromatography.26,27Data are expressed in micromoles per liter for water-solubleantioxidants and retinol and in micromoles per millimole oftotal lipids (the sum of cholesterol and triglycerides) forlipid-soluble compounds.
Measurements of Urinary Nicotine and Cotinine
Concentrations of nicotine and its metabolite, cotinine, inurine were quantified by high-performance liquid chromatography;the results are expressed in micromoles per liter.28
Clinical Protocols
Two separate clinical studies were performed. Both were approvedby the human studies committees of the medical centers involved,and informed consent was obtained from all subjects. Initially,we carried out a pilot study in which we recruited 24 subjects(16 who smoked one to two packs of cigarettes per day and 8nonsmokers). Twelve of the subjects were apparently healthy;six of the smokers had angiographically or clinically documentedcoronary artery disease; and six subjects (two nonsmokers andfour smokers) had hypertension. Patients with these conditionswere receiving medical therapy. No subjects took vitamin supplements.Blood was collected on a single occasion after an overnightfast for measurement of F2-isoprostanes.
After the completion of the pilot study, we carried out a second,more detailed, validation study for which we recruited 10 smokers(who smoked more than 1.5 packs of cigarettes per day) and 10nonsmokers matched with the smokers for age and sex. The nonsmokerswere not exposed to passive smoke at work or at home. Five menand five women made up each of the study groups. All the subjectsincluded in the study had a normal physical examination, electrocardiogram,and blood-chemistry tests (complete blood count and the 18 testsof the Sequential Multiple Analyzer 18 system) and had no apparentunderlying disease. None were taking medications or vitaminsupplements.
The study protocol was as follows. On day 1, the smokers werestudied at 8 a.m. and were not allowed to smoke or eat beforethe first blood sample was obtained. After blood was obtainedfor measurements of F2-isoprostanes and circulating antioxidants,the subjects smoked three cigarettes during a 30-minute period,after which blood was again obtained for analysis of F2-isoprostanes.The same procedure was repeated on day 3 of the study. The averageof the two measurements of F2-isoprostanes in blood obtainedon days 1 and 3 is reported here. The median variance in thelevels of F2-isoprostanes measured on separate days did notexceed 12 percent. A 24-hour urine specimen was collected onday 1 for measurement of F2-isoprostane metabolites; urine wasalso collected on day 1 for measurement of nicotine and cotinine.For nonsmokers, blood was obtained for measurement of F2-isoprostaneson days 1 and 3 of the study and for measurement of antioxidantson day 1. Urine was collected on day 1 for measurement of F2-isoprostanemetabolites.
The subjects who smoked were then instructed to cease smokingfor a period of two weeks. No nicotine-replacement therapy (suchas nicotine patches) was used. Two of the 10 smokers were unableto quit smoking. After the cessation of smoking, blood was againobtained on two separate days for the measurement of F2-isoprostanes.Urine samples were collected at the end of the two-week periodof abstinence from smoking for measurement of nicotine and cotinineto monitor compliance.
Statistical Analysis
In the pilot study, data were analyzed with the Wilcoxon rank-sumtest. In the second study, smokers and nonsmokers were matchedin terms of age and sex. Data were therefore analyzed usingthe Wilcoxon signed-rank test. Tests of the Spearman (nonparametric)correlation were used to assess the association of F2-isoprostanelevels with other measurements. All data are expressed as means±SD. Differences were considered statistically significantif the P value was 0.05 or lower.
Results
Pilot Study
Initially, we compared levels of F2-isoprostanes in 16 smokersand 8 age-matched nonsmokers. All but one of the subjects weremale. The smokers ranged in age from 43 to 72 years (mean, 55.2±8.3).The nonsmokers ranged in age from 47 to 71 years (mean, 54.4±8.7).The smokers smoked an average of 1.4±0.5 packs of cigarettesper day (28±10 cigarettes). The cumulative total of cigarettessmoked ranged from 20 to 100 pack-years. As shown in Table 1,levels of free F2-isoprostanes in the circulation and F2-isoprostanesesterified to plasma lipids were significantly higher in thesmokers than in the nonsmokers (P = 0.02 and P = 0.05, respectively).
Table 1. Clinical and Laboratory Data on Subjects in the Pilot Study.
Validation Study
The finding that levels of F2-isoprostanes in the circulationwere significantly higher among the smokers in the pilot studyprovided the impetus to conduct a more extensive, well-controlledstudy, not only to confirm the results of the pilot study butalso to determine the short-term effects of smoking and theeffects of abstinence from smoking on the production of F2-isoprostanes.Unlike the pilot study, the validation study enrolled only youngpersons who had no apparent underlying disease and were takingno medications. In addition, equal numbers of male and femalesubjects were studied. The smokers in this study all smokedmore than 1.5 packs of cigarettes per day (mean, 1.85±0.25packs per day [37±5 cigarettes]). The smokers had from4 to 50 pack-years of smoking (mean, 22±11). A varietyof brands of cigarettes were used, but the mean tar contentwas 10.8±3.4 mg per cigarette and the mean nicotine contentwas 0.8±0.2 mg per cigarette. Additional characteristicsof the subjects are summarized in Table 2.
Table 2. Clinical and Laboratory Data on Subjects in the Validation Study.
Measurements of F2-Isoprostanes
The levels of free F2-isoprostanes in plasma from smokers (242±147pmol per liter) were significantly higher than those measuredin age- and sex-matched nonsmokers (103±19 pmol per liter,P = 0.02) (Figure 2). The levels of F2-isoprostanes esterifiedto lipids in plasma from smokers (574±217 pmol per liter)were also significantly higher than those measured in nonsmokers(345±65 pmol per liter, P = 0.03) (Figure 2). No associationwas found between levels of F2-isoprostanes in smokers and sex,age, weight, height, serum cholesterol or triglyceride levels,history of smoking in pack-years, number of cigarettes smokedper day, or the tar and nicotine content of the cigarettes smoked.
Figure 2. Levels of Free and Esterified F2-Isoprostanes in Plasma from Smokers and Nonsmokers.
The dots representing subjects who smoked are each connected to a dot representing a nonsmoker matched to the subject for age and sex.
Measurement of the urinary excretion of prostanoid metaboliteshas proved to be an extremely reliable method of assessing theendogenous production of prostanoids.29 Therefore, we soughtfurther confirmation of the overproduction of F2-isoprostanesin smokers by quantifying the urinary excretion of F2-isoprostanemetabolites.25 The urinary excretion of the metabolites in smokers(870±509 pmol per millimole of creatinine) was significantlyhigher than that in nonsmokers (415±155 pmol per millimoleof creatinine, P = 0.05). In addition, we found a significantcorrelation (r = 0.97, P<0.001) between the urinary excretionof F2-isoprostane metabolites and circulating concentrationsof free F2-isoprostanes in smokers and nonsmokers (Figure 3).
Figure 3. Levels of Free Circulating F2-Isoprostanes and the Urinary Excretion of an F2-Isoprostane Metabolite in Smokers () and Nonsmokers (•).
Each dot represents a different subject. The plasma levels of F2-isoprostanes and the urinary level of F2-isoprostane metabolite were highly correlated (r = 0.97, P<0.001). There was a significant difference between smokers and nonsmokers with regard to the levels of both substances (P0.05).
We next determined the short-term effect of smoking on circulatinglevels of F2-isoprostanes in the 10 smokers. We found no significantdifferences in the levels measured in blood obtained in themorning before smoking and the levels measured immediately afterthe subjects smoked three cigarettes during a 30-minute period.The mean plasma level of free F2-isoprostanes was 242±147pmol per liter before smoking and 237±117 pmol per literafter smoking (P = 0.43). The mean level of F2-isoprostanesesterified to plasma lipids was 574±217 pmol per literbefore smoking and 624±214 pmol per liter after smoking(P = 0.20).
Effect of Abstinence from Smoking on F2-Isoprostane Levels
Eight of the 10 smokers who entered this study were able tostop smoking for two weeks. Levels of both free and esterifiedF2-isoprostanes in the plasma of these eight subjects aftertwo weeks of abstinence from smoking were significantly lowerthan the levels measured during smoking (Figure 4). The meanfree F2-isoprostane level during smoking was 250±156pmol per liter; after two weeks of abstinence it had fallento 156±67 pmol per liter (P = 0.03). The mean level ofF2-isoprostanes esterified to plasma lipids during smoking was624±214 pmol per liter, and after two weeks of abstinenceit had fallen to 469±108 pmol per liter (P = 0.02). Cessationof smoking was confirmed by the finding that levels of urinarynicotine and cotinine measured during the smoking period (1.17±0.87µmol per liter and 1.05±0.65 µmol per liter,respectively) fell to undetectable levels (<0.03 µmolper liter for each compound) in each subject after two weeksof abstinence from smoking.
Figure 4. Percent Change in the Levels of Free and Esterified F2-isoprostanes in Plasma from Smokers after Two Weeks of Abstinence from Smoking.
Each dot on the right represents the change for an individual subject.
Levels of Circulating Antioxidants
Plasma levels of uric acid, alpha-tocopherol, gamma-tocopherol,alpha carotene, beta carotene, lycopene, lutein and zeaxanthin,cryptoxanthin, total carotenoids, and retinol did not differsignificantly between smokers and nonsmokers in the validationstudy (P>0.05). In accordance with the results of previousstudies,12,13,14 plasma ascorbate levels were significantlylower in the smokers (25.8±18.4 µmol per liter)than in the nonsmokers (54.3±19.1 µmol per liter,P = 0.002); in this study we did not control for vitamin C intake.
Discussion
Our finding that the production of F2-isoprostanes is higherin smokers than in nonsmokers provides compelling evidence thatsmoking causes oxidative modification of biologic componentsin humans. This conclusion is greatly strengthened by the findingthat levels of F2-isoprostanes in the smokers fell significantlyafter two weeks of abstinence from smoking. These results providea basis for hypotheses that link oxidative damage of criticaltarget biomolecules to the pathogenesis of diseases caused bysmoking.
The results of previous studies of smoking and oxidative injuryin humans have been conflicting and difficult to interpret.The most widely used test for oxidative stress is the measurementof malondialdehyde, a product of lipid peroxidation, by thethiobarbituric acid–reacting substances assay.19 Haratsand colleagues found no significant differences between smokersand nonsmokers in the levels of thiobarbituric acid–reactingsubstances in freshly prepared plasma or LDL.10 However, othergroups have reported that the levels of thiobarbituric acid–reactingsubstances are significantly higher in plasma from smokers thanin plasma from nonsmokers.16,30 The reason for these discrepanciesmay be that the measurement of thiobarbituric acid–reactingsubstances is not an accurate indicator of lipid peroxidationin biologic samples.19 Another method of assessing lipid peroxidationin vivo is the measurement of exhaled alkanes, such as ethaneand pentane; pentane exhalation has been reported to be higherin smokers.31 However, the accuracy of exhaled pentane as amarker of endogenous lipid peroxidation has been questioned.32
On the other hand, we have shown previously that circulatinglevels of F2-isoprostanes appear to provide an accurate measureof lipid peroxidation in vivo.20,22,23 In the current study,we found higher levels of both free F2-isoprostanes in the circulationand F2-isoprostanes esterified to plasma lipids in smokers thanin nonsmokers. The finding that levels of esterified F2-isoprostaneswere higher in smokers extends our previous findings from invitro studies that F2-isoprostanes are formed in plasma andLDL exposed to oxidative stress.33 As previously discussed,oxidative modification of LDL is thought to be a key processin the development of atherosclerosis. Thus, the finding thatplasma lipids from smokers have been modified by oxidation mayprovide a mechanistic link between cigarette smoking and atherogenesis.However, we did not show in this study that LDL itself was oxidativelymodified. Although the vast majority of circulating lipids areassociated with lipoproteins,34 further studies will be requiredto determine to what extent LDL and other lipoproteins are oxidativelymodified by cigarette smoking.
Interestingly, only slightly increased levels of F2-isoprostanes,or none, were found in some of the smokers studied. This findingis of interest in view of the fact that some people appear moreresistant than others to the toxic effects of smoking. The reasonfor this apparent heterogeneity in susceptibility to the oxidativeeffects of smoking is unclear. However, the ability to identifysmokers who have only slightly increased levels of F2-isoprostanesand those with more marked overproduction of F2-isoprostanesmay make it possible to explore the reasons for these differences.We did not find any relation between F2-isoprostane productionand age, sex, number of pack-years of smoking, or number ofcigarettes smoked per day. It is possible that differences inantioxidant defense capacity affect susceptibility to the oxidanteffects of cigarette smoke. In this regard, we did find, ashave others, that smokers had substantially lower plasma concentrationsof ascorbate than nonsmokers. Because we did not control forvitamin C intake, however, it remains to be determined whetherthis relation reflects increased utilization of ascorbate bysmokers or decreased intake.
Supported by grants (GM-42056, GM-15431, HL-49954, ES-00267,and RR-00095) from the National Institutes of Health. Dr. Morrowis a Howard Hughes Medical Institute Physician Research Fellowand the recipient of a Research Foundation Award from the InternationalLife Sciences Institute. Dr. Frei is the recipient of a FutureLeader Award from the International Life Sciences Institute–NutritionFoundation.
We are indebted to William Zackert, Aiping Wu, Gary Cunningham,Elizabeth Shipp, Gwenn Sobo, Vincent Daniel, Timi Mannion, andJim Anderson for expert technical assistance; to Kathy Cunninghamfor assistance in the preparation of the manuscript; and toDr. Robert Parker for advice on the statistical analysis ofdata.
Source Information
From the Departments of Medicine and Pharmacology (J.D.M., A.W.L., J.A.O., L.J.R.) and the Division of Biostatistics, Department of Preventive Medicine (Y.S.), Vanderbilt University, Nashville; the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston (B.F., S.M.L.); the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (J.M.G.); and the Section of Cardiology, Brockton–West Roxbury Veterans Affairs Medical Center and Harvard Medical School, Boston (W.E.S.).
Address reprint requests to Dr. Morrow at the Departments of Pharmacology and Medicine, 506 MRB, Vanderbilt University, Nashville, TN 37232-6602.
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Previous
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