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(Chest. 1999;115:684-690.)
© 1999 American College of Chest Physicians

Effect of Vitamin E on Exhaled Ethane in Cigarette Smokers*

Michael P. Habib, MD, FCCP; Laura J. Tank, BS; Lisa C. Lane, BS and Harinder S. Garewal, MD

* From the Pulmonary Medicine and Oncology Sections of the Veterans Affairs Medical Center and the University of Arizona, Tucson, AZ.


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: We hypothesized that micronutrient antioxidant intake may be one factor determining the development of significant COPD. Vitamin E was administered to smokers to determine if exhaled ethane was reduced and if ethane correlated with measures of lung function.

Study design: Longitudinal placebo lead-in trial with posttreatment observation period.

Setting: Tucson Veterans Affairs Medical Center.

Participants: Twenty-nine current stable smokers having no interest in smoking cessation.

Interventions: Spirometry, exhaled breath ethane measurements, and vitamin E and ß-carotene plasma levels followed by 3 weeks of placebo with repeat plasma vitamin levels and ethane measurements; next, 3 weeks of vitamin E (dl-{alpha}-tocopherol), 400 IU po bid followed by plasma vitamin levels and breath ethane measurements; finally, 3 weeks without vitamins followed by breath ethane and plasma vitamin levels.

Results: Vitamin E treatment did not reduce ethane significantly. Exhaled ethane levels (mean + SD: pm/min/kg) were as follows: baseline, 7.39 ± 5.39; after run-in period, 6.86 ± 4.09; after vitamin E, 6.36 ± 3.02; and final, 7.23 ± 4.63. After vitamin E therapy, a significant negative correlation existed between exhaled ethane and FEV1/FVC. Pack-years of smoking at baseline and after vitamin E were significantly associated with ethane exhaled. Initial lung function was not significantly negatively associated with vitamin E-induced changes in exhaled ethane but a negative trend was found.

Conclusions: Vitamin E alone, unlike the combination of vitamins C, E, and ß-carotene, failed to reduced exhaled ethane in cigarette smokers. Exhaled ethane was correlated with pack-years of smoking. Smokers whose ethane values were found to fall the most tended to have better preserved lung function.

Key Words: antioxidants • COPD • vitamin E


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Although cigarette smoking is the most important factor in the development of COPD, the mechanisms by which cigarette smoke leads to obstructive airways disease is not fully understood. Approximately 15 to 20% of cigarette smokers develop clinically significant COPD.1 Understanding the mechanisms of smoking-induced injury may allow us to predict which smokers will progress to develop significant disease and the attendant complications. This may allow us to find ways to retard or prevent the development of injury.

Oxidative or free radical injury of respiratory cells is believed to a significant contributor to the development of COPD.2 Cigarette smoke contains approximately 1015 oxygen free radicals per puff.3 Although the lung supports significant antioxidant defense strategies designed to balance the effects of the oxidant-rich gaseous milieu that is inspired air, the increased oxidant load from cigarette smoke may result in a cascade of events culminating in activation of neutrophils and macrophages and resultant increases in proteases. The resulting protease/antiprotease imbalance may cause structural lung damage and the development of lung disease.4 ,5 ,6

The putative use of antioxidants as preventive agents for the development of COPD has been promulgated based on the proposed relationships among oxidants, tissue injury, and disease. Recent studies examining the role of antioxidants in large populations have shown an inverse association between lung disease and antioxidant vitamin intake.7 ,8 ,9

Previously we have shown that the alkane, ethane, is found in increased amounts in the breath of smokers as compared with nonsmokers.10 ,11 Ethane gas was shown by Reilly et al12 in 1974 to be a hydrocarbon byproduct of lipid peroxidation. Other investigators have also found increased evidence of oxidant activity in smokers.13 ,14 ,15 ,16 Previous work from our laboratory has shown that supplementation of smokers' diets with a combination of three micronutrient antioxidants, vitamin C, vitamin E, and ß-carotene, decreases exhaled ethane levels.11

In that previous study, the ability of the micronutrient antioxidants to reduce exhaled ethane was correlated closely with their lung function as measured by percent predicted FEV1.11 The better preserved the FEV1 in these smokers, the greater was the reduction in exhaled ethane after supplementation. We hypothesized that even when antioxidants are administered, they may only show an effect on ethane if they can be incorporated into the appropriate pathways and correct any oxidant-antioxidant imbalance. We have proposed that a reduction in exhaled ethane after antioxidant supplementation is a manifestation of such an effect and results in preservation of lung function. As a follow-up of our initial study, the current study examines the effects of vitamin E alone on exhaled breath ethane in smokers.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Participants were recruited from the patients and staff of the Tucson Veterans Affairs Medical Center as well as from the community. Based on power curve analysis and data from our previous work,11 a sample of 28 to 32 subjects was considered necessary to show a difference of slightly < 1 SD in exhaled ethane content based on an 80% power to detect this difference with {alpha} = 0.05.17 To be eligible, participants had to be cigarette smokers > 20 years of age and in good general health. All subjects signed informed consent that had been approved by the Institutional Review Board of the University of Arizona. Potential participants who had any history of diabetes, liver disease, lung cancer or any ongoing cancer, chronic illness, or alcohol/drug abuse were ineligible.18 Each participant was interviewed to obtain medical history, dietary habits using a food frequency questionnaire,19 smoking habits, and given a consent form to read and sign. Each enrolled study patient was asked to fast at least 8 h and refrain from smoking at least 3 h prior to each ethane measurement and blood collection.10

Compliance with taking the vitamin was confirmed by pill count and blood levels.

Each subject was studied on four occasions, 3 weeks apart. On each visit, exhaled breath ethane was measured and samples of serum were taken for measurement of vitamin E and ß-carotene. Between visits 1 and 2, subjects were asked to refrain from taking supplemental vitamins and were given a placebo to take for the 3-week run-in period. This was included to assess compliance. Between visits 2 and 3, subjects took vitamin E (dl-{alpha}-tocopherol; 400 IU bid; Roche Vitamins Inc), again refraining from the use of other vitamin supplements. After visit 3, they were asked to refrain from using supplemental vitamins for the next 3 weeks until after the final samples were collected.

Breath ethane was collected and sampled as previously described.11 Briefly, seated subjects breathed hydrocarbon-free air (Ultra Zero Air; Tucson, AZ) via a one-way valve (Hans-Rudolf; Kansas City, MO) from a five-layer reservoir bag (Calibrated Instruments; Hawthorne, NY) for a total of 10 min. During the first 8 min, subjects were asked to take vital capacity breaths to completely flush out the lungs with the inspirate. This 8-min sample was then discarded to remove all room air from the lungs. The exhalate from the last 2 min of this 10-min breathing period was collected in a second five-layer bag that was analyzed for ethane content. Ethane content of the hydrocarbon-free air was also measured to determine background ethane content.

The exhalate collected in the bag was drawn through duplicate cold traps of activated charcoal at - 70°C and 400 mL/min for 15 min. We had determined previously that this flow rate was able to trap ethane as efficiently as a flow rate of 200 mL/min. Each cold trap adsorbed the ethane from 6 L of exhalate. The remaining volume of exhalate in the five-layer bag was quantitated using a spirometer. The five-layer bags were flushed with hydrocarbon-free air and evacuated under vacuum after each use.

Immediately after the ethane was collected and while the cassettes were still very cold, the charcoal from each trap was poured into a 13.27-mL test tube that was quickly sealed with an open screw top housing a 13-mm TFE/silicone septum (Alltech; Deerfield, IL). The two test tubes were heated for 3 min at 250°C and were agitated from time to time to liberate all of the collected ethane. Five milliliters of the headspace gas in each test tube was removed using a calibrated precision sampling syringe (Alltech) and injected into the column of a gas chromatograph (Hewlett-Packard 5890; Palo Alto, CA) connected in line to an integrator (Hewlett-Packard 3393A). The column was a 2-m long glass column packed with a carbon molecular sieve (Carbosphere 60/80; Alltech) maintained isothermal at 220°C. Helium flow rate was 20 mL/min and retention time under these conditions was 5.30 min. Calibration was performed with two known aliquots of an ethane/nitrogen standard (Scotts Specialty Gases; San Bernadino, CA). Back calculation of the total ethane content in the headspace was then determined and the background ethane content of the inspirate was subtracted from the measured value. The mean of the duplicate samples was used for analysis. The total exhaled ethane was determined from the ethane content of the 6-L sample, the subject's weight, the background ethane content of the inspirate, and expressed as picomoles per minute per kilogram of body weight.

Approximately 15 mL of venous blood was drawn into sodium heparin tubes (Vacutainer; St. Louis, MO) from each subject on each of the four visits. These tubes were put on ice in the absence of light for 20 min to be fully chilled. The whole blood was then spun down in a centrifuge (National Labnet Co; Woodbridge, NJ) at 2,000 RPM for 10 min to isolate the plasma. The plasma was then pipetted into 2-mL microcentrifuge tubes (Fisher Scientific; Los Angeles, CA) wrapped in foil to keep out any light, and stored at -70°C. Concentrations of vitamin E and ß-carotene were measured as previously described.11 ,20


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The demographic profiles of the subjects recruited for this study appear in Table 1 . Most subjects were male (86%), reflecting the largely male population of patients at the Veterans Affairs Medical Center. They ranged in age from 42 to 75 years with the mean (± SD) being 59.5 (± 10.4) years. These subjects smoked a mean (± SD) of 50.9 (± 20.52) pack-years overall with a range of between 7.5 and 90 pack-years. Mean (± SD) FEV1 as percent predicted was 78.6% (± 21.6) with a range from 40 to 121%. The Mean FEV1/FVC ratio was 63.9% with a range of 49 to 86%.


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  		Table 1. Demographics

 
The results of the food frequency questionnaire showed an average daily vitamin A intake of 8,996.9 IU, a vitamin C intake of 115.2 mg, and vitamin E intake of 8.4 tocopherol equivalents (Table 2 ). Total caloric intake was within the acceptable normal range.


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  		Table 2. Daily Dietary Intake as per Food Frequency Questionnaire

 
There were no statistically significant differences in ethane values measured at any time point. Values for exhaled ethane were (mean ± SD)(pm/min/kg) as follows: at baseline (study entry), 7.39 ± 5.39; postplacebo run-in, 6.86 ± 4.09; after vitamin E, 6.36 ± 3.02; and final, 7.23 ± 4.63. Since ethane values at study entry were performed when vitamin intake was uncontrolled, ethane exhaled may be influenced by both prooxidant and antioxidant vitamins. Since vitamin intake was better controlled at the last three time points, it is on these three time points that we concentrate our analysis and discussion.

Fig 1 shows the association between pack-years and exhaled ethane level after placebo run-in (top, A), after vitamin E (center, B), and at the final visit (bottom, C). At all time points, there was a positive association between oxidant load and exhaled ethane. These correlations were statistically significant only after vitamin E treatment (Fig 1 , center, B).



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  		Figure 1. Effect of pack-years of smoking on exhaled ethane after placebo run-in (top, A), after vitamin E treatment (center, B), and at final visit (bottom, C). After supplementation with vitamin E (center, B), there was a statistically significant positive correlation between exhaled ethane and pack-years of smoking.

 
Fig 2 shows the relationship between pack-years and one measurement of lung function (FEV1/FVC). As expected, there was a significant negative association between these two variables.



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  		Figure 2. As expected, pack-years of smoking was inversely related to lung function as measured by the FEV1/FVC ratio.

 
Exhaled ethane was negatively associated with FEV1/FVC in general (Fig 3 ), but this negative correlation achieved statistical significance only after vitamin E intake (Fig 3 , center, B). The negative association between exhaled ethane and FEV1 percent predicted was also observed at all time points but never achieved statistical significance.



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  		Figure 3. Relationship between exhaled ethane and lung function as measured by FEV1/FVC ratio after placebo run-in period (top, A), after 3 weeks of vitamin E (center, B), and at final visit (bottom, C). There was a negative association between these two variables that was statistically significant after vitamin E supplementation (center, B). See text for discussion.

 
The relationship between lung function and changes in exhaled ethane after vitamin E alone were not statistically significant (Fig 4 ), but there appeared to be a negative slope to this relationship.



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  		Figure 4. The relationship between vitamin E-induced changes in exhaled ethane and measurement of lung function was not statistically significant. See Discussion section for details.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Evidence of increased lipid peroxidative activity in smokers has been shown by Petruzzelli et al,13 Karla et al,14 Morrow et al,15 by our laboratory,10 ,11 and by Hoshino et al.16 This increased free radical activity has been attributed to cigarette smoke, inflammation, and infections.21 Although cigarette smoking is the major risk factor for the development of COPD, not all cigarette smokers progress to develop clinically significant COPD. It is estimated that 10 to 20% of cigarette smokers will progress to clinically significant COPD.1

What factor or factors determine which smokers will be selected to have a rapid decline in lung function have yet to be determined. The role of diet has been studied since antioxidant defenses are believed to be important in protecting the lung from the effects of the high oxidant load to which the lung is exposed. Recent epidemiologic data from Britton et al7 have supported the notion of antioxidant intake being a factor in the development of lung disease. In that large epidemiologic study of middle-aged people from central England, both vitamin E and vitamin C intake were associated with preservation of lung function. The authors noted that the protective effect of vitamin C was greater than for vitamin E. Another study by Rautalahti et al8 showed reduced respiratory symptoms being correlated with increased intake of vitamin E and ß-carotene.

Measurement of exhaled alkanes has been used by us and others16 ,18 ,22 ,23 as a noninvasive marker of lipid peroxidation. We favor ethane over pentane as a measure of lipid peroxidation because of the more rapid metabolism of pentane by animals and man.24 ,25 ,26 In addition, mass spectroscopic analysis of human exhalate demonstrates the presence of significant amounts of isoprene, which may be mistaken for n-pentane during gas chromatographic analysis rendering pentane quantification complex.27

We have found that ethane is affected by cigarette smoke10 and diet,28 although others have not found the latter.29 A 3-h abstinence from cigarettes and an 8-h fast have yielded the most consistent results in the past in our laboratory.10 Since patients with obstructive lung disease may trap gas, ambient air, which contains significant amounts of ethane, may contaminate the collected sample and the more severe the obstruction, the greater the risk that ambient trapped air will contaminate the sample after the washout period. To circumvent this, we have used a particularly long washout period with hydrocarbon-free air and have employed vital capacity breaths at multiple times during the 8-min washout. We have found that hydrocarbon-free air is required since ambient air contains significant amounts of ethane, and the ambient air ethane content may change very quickly from moment to moment, particularly if the air intake vent is near a parking lot or other such source of pollution.

The values for exhaled ethane we report in this article are higher than what has been reported in the literature for healthy nonsmoking subjects. A review by Kneepkens et al18 indicates that the range for ethane exhalation in nonsmoking adults is between 1.4 to 3.4 pm/kg/min. These values are lower than our results in smokers but in keeping with our previous reports10 ,11 about ethane exhalation in never smokers. The higher values for exhaled ethane found in this study may be representative of the fact that smokers have altered oxidant/antioxidant ratios, and hence, increased lipid peroxidative activity.

Cigarette smokers have been shown to have lower levels of micronutrient antioxidants through poor intake, increased metabolism, or their oxidation as they perform their purported duties of reducing antioxidant stress.30 In the current study, we found no correlation between ß-carotene levels on entry into the study and measures of lung function (data not shown). Also, we did not find a correlation between vitamin E levels at entry and lung function measurements. However, damage to lungs from smoking occurs over many years, and one would not expect to see a correlation between a blood level at a single point in time and measures of lung function even if the hypothesis was correct. Thus, vitamin E and ß-carotene levels by themselves would be expected to be poor markers of the presence of cigarette-induced diminutions of lung function. (We did not assay serum vitamin C levels since, being water soluble, its fluctuation from moment to moment is very wide).

However, we did find a negative correlation between FEV1/FVC and exhaled ethane after vitamin E supplementation (Fig 3 , center, B). After replacement of vitamin E, a negative correlation between exhaled ethane levels and FEV1/FVC was detected that reached statistical significance (p < 0.037). Although not reported in our previous study, there was also a negative association between FEV1/FVC and exhaled ethane after replacement of all three antioxidants. That negative association did not reach statistical significance probably because the number of subjects studied was very small (n = 10). Furthermore, in that study as in the present one, there was no association found between FEV1/FVC and exhaled ethane before antioxidant administration. The observation that a negative association was found between FEV1/FVC ratios and exhaled ethane only after antioxidant replacement may be explained by a hypothesis based on the consistent finding that the levels of micronutrients found in smokers, are usually low and do not correlate with dietary intake. Thus, a wide variability in micronutrient levels would be expected, and the resultant effects on ethane production would be variable as well. However, once antioxidant levels are raised by supplementation such that they are high and the antioxidant effects are at their maximum, variations in ethane would be the result of oxidant effect rather than antioxidant effect. Under this scenario, the negative relationship between exhaled ethane and lung function would be exposed as it appears to be from both of our studies. Examination of Fig 3 , center (B), also reveals less scatter of ethane values than can be found in any of the other panels of Fig 3 supporting our hypothesis. Additional support for this hypothesis comes from the observation that 3 weeks after these subjects had resumed their previous nutritional habits with no further supplementation, no correlation was found between vitamin E levels and lung function (Fig 3 , bottom, C). To further support the above contention, the analysis comparing pack-years with exhaled ethane also shows statistical significance only after vitamin E supplementation (Fig 1 , center, B).

Although the reduction in ethane after vitamin E supplementation was not statistically significant, a trend for a negative association between measures of lung function and the changes in lung ethane is to be noted (Fig 4 ). This result is consistent with our previous observation in which the reduction in exhaled ethane induced by vitamin E, vitamin C, and ß-carotene correlated significantly with preserved lung function in smokers.11 We explain the absence of a statistically significant correlation as follows: first, we found that vitamin E alone does not lower ethane levels as much as a combination of the agents or even one of the other nutrients. This would be in keeping with the study by Britton et al7 in which the effect of vitamin C alone was greater than vitamin E. It may be that both vitamin C and vitamin E and possibly ß-carotene are needed for effective antioxidant activity in that redox cycling occurs within these agents.31 ,32 Second, despite our power analysis used to determine sample size, our sample size may not have been sufficient to detect statistical significance given the smaller than anticipated reduction in ethane accruable to vitamin E alone. We had based our power analysis on the observed reduction in exhaled ethane found in our previous publication in which a combination of antioxidant vitamins had been administered to smokers.11

Pack-years, as expected, were negatively correlated with lung function (Fig 2 ). In addition, as noted, after vitamin replacement, pack-years were significantly associated with exhaled ethane levels (Fig 1 , center, B). In our previous study,11 pack-years were significantly correlated with exhaled ethane only after replacement of micronutrient antioxidants. In this earlier study, a similar positive trend was also present prior to nutrient replacement, but it failed to reach statistical significance. The results from this study imply an association between oxidant load and exhaled ethane, as well as a negative association between exhaled ethane and lung function.

We conclude by contending that vitamin E alone does not significantly attenuate the effects of cigarette smoke on exhaled ethane. Exhaled ethane corresponds to oxidant load overall. After vitamin E is administered, those subjects demonstrating the largest falls in exhaled ethane appear to have better lung function. Exhaled ethane correlates negatively with measures of lung function after vitamin E replacement. These results suggest that vitamin E alone has a smaller effect than we previously noted when all three micronutrient antioxidants were supplemented simultaneously.11 More studies need to be done, perhaps with a larger population, to further delineate the role, if any, of vitamin E treatment on alterations in lung function and the development of COPD in smokers.


   Footnotes
 
Supported by the Arizona Disease Control Research Commission and the Department of Veterans Affairs. Vitamins and placebo were supplied by Roche Vitamins Inc.

Correspondence to: Michael Habib, MD, FCCP, Pulmonary Section (1-111A), VAMC, 3601 S Sixth Ave, Tucson, AZ, 85723; e-mail: mhabib@resp-sci.arizona.edu

Received for publication June 11, 1998. Accepted for publication October 1, 1998.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Exhaled Ethane, a Marker of Lipid Peroxidation, Is Elevated in Chronic Obstructive Pulmonary Disease
Am. J. Respir. Crit. Care Med., August 1, 2000; 162(2): 369 - 373.
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 Am. J. Respir. Crit. Care Med.Home page
P. PAREDI, S. A. KHARITONOV, D. LEAK, P. L. SHAH, D. CRAMER, M. E. HODSON, and P. J. BARNES
Exhaled Ethane Is Elevated in Cystic Fibrosis and Correlates with Carbon Monoxide Levels and Airway Obstruction
Am. J. Respir. Crit. Care Med., April 1, 2000; 161(4): 1247 - 1251.
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 ThoraxHome page
I. Rahman, E. Swarska, M. Henry, J. Stolk, and W. MacNee
Is there any relationship between plasma antioxidant capacity and lung function in smokers and in patients with chronic obstructive pulmonary disease?
Thorax, March 1, 2000; 55(3): 189 - 193.
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