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Journal of the American College of Nutrition, Vol. 23, No. 2, 141-147 (2004)
Published by the American College of Nutrition

Original Research

Plasma C-Reactive Protein Concentrations in Active and Passive Smokers: Influence of Antioxidant Supplementation

Gladys Block, PhD, Christopher Jensen, PhD, Marion Dietrich, PhD, Edward P. Norkus, PhD, Mark Hudes, PhD and Lester Packer, PhD

Division of Community Health and Human Development, School of Public Health (G.B., C.J., M.D.), Department of Nutritional Sciences (M.H.), University of California, Berkeley, Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles (L.P.), California, Department of Medical Research, Our Lady of Mercy Medical Center, Bronx (E.N.), New York

Address reprint requests to: Gladys Block, PhD, 426 Warren Hall, School of Public Health, University of California, Berkeley CA 94720. E-mail: Gblock{at}berkeley.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Objective: C-reactive protein (CRP) may directly affect the progression of atherosclerosis, and therefore, may be a target for reducing disease risk. The objective was to determine whether antioxidant supplementation reduces plasma CRP in active and passive smokers.

Design: Randomized, double-blind, placebo-controlled, parallel group trial with 2 months exposure to study supplements.

Setting: Berkeley and Oakland, California.

Subjects: Healthy adult men and women, consuming <4 daily servings of fruits and vegetables, and who were actively or passively exposed to cigarette smoke. Analysis was limited to participants with detectable baseline CRP concentrations and no evidence of inflammation associated with acute illness at baseline or follow-up as reflected in CRP elevations (>=10.0 mg/L). A total of 1393 individuals were screened, 216 randomized, 203 completed the study, and 160 were included in the analysis.

Interventions: Participants were randomized to receive a placebo or vitamin C (515 mg/day) or antioxidant mixture (per day: 515 mg vitamin C, 371 mg {alpha}-tocopherol, 171 mg {gamma}-tocopherol, 252 mg mixed tocotrienols, and 95 mg {alpha}-lipoic acid).

Measures of Outcome: Change in plasma CRP concentration.

Results: Vitamin C supplementation yielded a 24.0% reduction (95% confidence interval, -38.9% to -5.5%, p = 0.036 compared to control) in plasma CRP, whereas the antioxidant mixture and placebo produced a nonsignificant 4.7% reduction (-23.9% to 19.3%) and 4.3% increase (-15.1% to 28.2%), respectively. Results were adjusted for baseline body mass index and CRP concentrations.

Conclusions: Plasma CRP itself may serve as a potential target for reducing the risk of atherosclerosis, and antioxidants, including vitamin C, should be investigated further to confirm their CRP-lowering and anti-inflammatory effects.

Key words: antioxidants, C-reactive protein, inflammation, vitamin C, vitamin E, atherosclerosis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
C-reactive protein (CRP) is an acute phase protein produced primarily by the liver in response to inflammatory cytokines such as interleukin-6 [1]. Prospective epidemiologic studies among asymptomatic individuals have shown plasma CRP to be predictive of future cardiovascular disease risk [2–12], reinforcing the view that cardiovascular disease involves an ongoing inflammatory response. While CRP is a marker of disease risk, emerging evidence also suggests that CRP has a direct effect on the progression of atherosclerosis [1]. These reported functions include an ability to bind and activate complement [13], induce expression of adhesion molecules as well as tissue factor [14,15], mediate LDL uptake of endothelial macrophages [16], induce monocyte recruitment into the arterial wall [17], enhance production of monocyte chemoattractant protein-1 [18], and induce expression and activity of plasminogen activator inhibitor-1 in aortic endothelial cells [19]. These findings raise the possibility that CRP itself may serve as a potential target for reducing the risk of atherosclerosis.

Cigarette smoking has been found to be associated with CRP elevations [2,9,11,20], therefore active and passive smokers may be appropriate targets for interventions aimed at lowering plasma CRP. Few clinical trials have assessed the impact of supplemental antioxidants on plasma CRP concentrations, and none have examined the effect in smokers. Vitamin E supplementation significantly lowered plasma CRP concentrations among type II diabetics [21,22], and healthy controls [21], while vitamin C did not [22]. This study reports on the impact of supplemental vitamin C, alone and in combination with {alpha}- and {gamma}-tocopherol, mixed tocotrienols, and {alpha}-lipoic acid, on plasma CRP concentrations among active and passive smokers.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects for this analysis were selected from a cohort of 129 cigarette smokers and 74 passive smokers (Fig. 1) who completed a randomized, double-blind, placebo-controlled, parallel group trial that examined the effects of antioxidant supplements on measures of oxidative stress among smokers [23,24]. The study design was approved by the institutional review boards of the University of California, Berkeley, and Kaiser Permanente Division of Research. Participants were recruited between June 1998 and June 1999 by local advertising from the communities of Berkeley and Oakland, CA., and by mailings to Kaiser Permanente health plan members. Signed informed consents were obtained from all subjects prior to study enrollment.



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  		Fig. 1. Flow chart for participating individuals.

 
Smokers were eligible for the original study if they smoked >=15 cigarettes/d for >=1 yr. Passive smokers were eligible if they had not smoked cigarettes in the prior year and were exposed indoors to the smoke of >=1 cigarette/d on >=5 d/wk. Exclusion criteria included self-reported consumption of >=4 servings/d of fruits and vegetables, >=2/d alcoholic drinks or history of alcohol abuse within the prior year; current pregnancy; hemochromatosis; history of kidney stones or other kidney diseases; cancer; stroke; myocardial infarction within the last 5 years; hepatitis; diabetes mellitus; human immunodeficiency virus infection; use of blood-thinning medications; and consumption of iron supplements or supplemental vitamin E in amounts exceeding 800 IU per day. Users of other vitamin/mineral supplements underwent a 5-wk washout period, prior to baseline collections, during which no supplements were allowed. As shown in Fig. 1, a total of 216 subjects were enrolled in the trial and 203 completed the study. This analysis was limited to data from participants who had detectable plasma CRP levels at baseline (>=0.18 mg/L) and who had no evidence of active inflammation associated with acute, infectious illness, at baseline or follow-up, as reflected in CRP elevations >=10.0 mg/L. These exclusions resulted in a sub-sample of 160 individuals that included 106 of the 129 active smokers and 54 of the 74 passive smokers. The proportions of subjects excluded from this CRP analysis were similar between treatment groups (Fig. 1). Use of medications that lower CRP such as statins, glitazones, fibrates, niacin, or fish oil was not specifically a part of the exclusion criteria for the study since CRP-lowering was a secondary endpoint of interest. However, a review of subject-reported medications identified a total of five subjects taking statins and none taking glitazones, fibrates, niacin or fish oil. Elimination of the five subjects taking statins in the data analysis did not substantially change the study findings nor statistical significance; therefore, the findings reported include the data from the five subjects taking statins.

Blood was drawn from participants during three clinic visits, with the first two visits 1 to 4 wks apart. At the second visit participants were randomly assigned to one of three treatment groups: (1) placebo control; (2) vitamin C (515 mg/d); or (3) antioxidant mixture (per day: 515 mg vitamin C, 371 mg RRR {alpha}-tocopherol, 171 mg {gamma}-tocopherol, 252 mg mixed tocotrienols, and 95 mg {alpha}-lipoic acid). A randomization sequence and assignment of participants to treatment groups was generated by computer. Randomization was stratified by gender, age, and body weight to assure balance on these factors across treatment groups. Investigators, study staff and participants were blinded to treatment assignments. Treatments were encapsulated and indistinguishable. Treatment assignments were kept concealed and were administered blinded. Separate study staff administered interventions and assessed outcomes and they too were blind to group assignments. The third blood draw took place after two months (an average of 58 days of study capsule intake) and capsule bottles were collected and unused capsules counted to assess supplementation compliance. Participants refrained from smoking for at least 1 hr before clinic visits and blood draws took place after fasting overnight for 12 hrs. Venous blood was drawn into Vacutainers (Becton Dickinson, Rutherford, NJ) containing EDTA as coagulant, centrifuged at 5° C for 10 minutes at 1,200 x g, protected from light, and stored at -70° C. Plasma aliquots for ascorbic acid were mixed 1:1 with freshly-prepared 10% (w/v) meta-phosphoric acid to stabilize ascorbic acid, protected from light and stored at -70° C. Concentrations of cotinine were determined by gas chromatography with nitrogen-phosphorus detection. Plasma ascorbic acid was determined spectrophotometrically using 2,4-dinitrophenylhydrazine as chromogen. Tocopherols and carotenoids were measured by reverse-phase high-performance liquid chromatography.

Plasma CRP concentrations were measured by radial immunodiffusion (The Binding Site Inc., San Diego, CA). Radial immunodiffusion involves the radial diffusion of a specific antigen (CRP) from a central well outward through an agarose gel containing the appropriate mono-specific antibody. During radial diffusion, antigen-antibody complexes are formed. At equilibrium, a stable, precipitated complex appears in the agarose gel as a visible ring some distance out from the central well. A linear relationship exists between the square of the ring diameter (measured to 0.1 mm) and the concentration of the antigen that was added to the central well. By measuring the radial immunodiffusion diameters of several different concentrations of a known antigen, run-specific standard curves were generated and used to quantitate the concentration of sample unknowns. Control samples, of known antigen concentration, were used to validate the daily (run-specific) standard curves. The CRP assay is sensitive to low values of plasma CRP, with a minimum detectable limit of 0.18 mg/L and a coefficient of variation of 6.2%. The assay detection limit is comparable to the detection limit of 0.15 mg/L cited for high-sensitivity CRP assays [25], and well below the detection limit of 3–5 mg/L for the standard clinical laboratory assay.

All participants completed a questionnaire related to smoking history and a Block98 food frequency questionnaire that produced estimates of macronutrient and micronutrient intakes.

The objective of this analysis was to ascertain the impact of antioxidant supplements, taken daily for 2 mo, on plasma CRP concentrations among active and passive smokers. The primary outcome measure was percent change in plasma CRP concentration. We hypothesized that the antioxidant mixture would be more effective in reducing CRP than either vitamin C alone or the placebo control. Differences in mean baseline characteristics and changes over time between the treatment groups were compared by one-way analysis of variance for continuous variables. Data were screened for possible violations of model assumptions of equal variances and normal distribution. Values for CRP and plasma beta carotene were log-transformed to more closely resemble a normal distribution. For categorical variables, differences in proportions between treatment groups at baseline were examined using chi-square tests. The interactions of treatment group and the covariates body mass index, smoking level (active or passive), and plasma antioxidant status were investigated with no evidence of interaction detected. Differences in the outcome measure, change in plasma CRP concentration, were compared by regression techniques and treatment effects were adjusted for baseline plasma CRP concentrations and body mass index. This analysis was conceived as hypothesis-generating, and as such, the alpha level was not adjusted for multiple comparisons. To account for multiple comparisons and obtain a test with an overall 5% procedure-wise error, the p-value for the change in plasma CRP can be compared to alpha = 0.016. Statistical analyses were conducted using SAS Version 9.0.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
No statistically significant differences in baseline characteristics between treatment groups were found for race, gender, age, body mass index, blood pressure, exposure to cigarettes, plasma cotinine concentration, dietary intake, plasma antioxidant status, and plasma lipids (Table 1). Changes in plasma cotinine and beta carotene concentrations during the treatment period did not differ significantly by treatment group (Table 2), suggesting that there was no differential exposure to cigarette smoke or dietary intake of food-sourced antioxidant nutrients between groups during the treatment period. The percentages of supplement capsules taken during treatment were 95%, 98%, and 95% for the antioxidant mixture, vitamin C, and control groups, respectively. Table 2 also shows the mean plasma ascorbic acid and {alpha}- and {gamma}-tocopherol concentrations at baseline and follow-up. As expected, mean plasma {alpha}-tocopherol concentration increased significantly only in the group taking the antioxidant mixture. Similarly, mean plasma ascorbic acid concentrations increased significantly only in the treatment groups taking the antioxidant mixture and vitamin C alone. Mean {gamma}-tocopherol concentrations were lower in all treatment groups at follow-up compared to baseline, however none of these changes were statistically significant.


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  		Table 1. Baseline Characteristics of Study Participants*

 

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  		Table 2. Plasma Cotinine and Antioxidant Concentrations at Baseline and Follow-Up*

 
As shown in Table 3, when adjusted for baseline plasma CRP and body mass index, mean plasma CRP concentrations were reduced by 24.0% in the vitamin C supplemented group (p = 0.036 in comparison to change observed in the control group), with a non-significant 4.7% reduction observed in those taking the antioxidant mixture, and a 4.3% increase seen among controls.


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  		Table 3. Change in Plasma CRP Concentrations*

 

   DISCUSSION
 
This is the largest study on the effect of vitamin C on plasma CRP, and the first study that we are aware of to show a CRP-lowering effect of vitamin C supplementation. The biologic rationale for this effect may be found in a recent report that vitamin C suppresses tumor necrosis factor-{alpha} (TNF{alpha})-induced nuclear factor-{kappa}B (NF{kappa}B) activation [26]. NF{kappa}B regulates genes that encode for pro-inflammatory factors including cytokines. Suppression of TNF{alpha}-induced NF{kappa}B activation, leading to reduced cytokine and CRP production, may account for the CRP-lowering effect of vitamin C that we observed.

The fact that CRP lowering was observed with 515 mg/d vitamin C in this study, but not with a comparable dose in type II diabetics [22] (Table 4), may point to different vitamin C requirements for CRP lowering between smokers and diabetics, or to other differences in subject characteristics. The different CRP responses to vitamin C in smokers and type II diabetics [22] also may reflect underlying differences in oxidative stress and transcription factor sensitivity to oxidative stress.


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  		Table 4. Antioxidant Clinical Trials with Plasma CRP as an Endpoint

 
The fact that vitamin E in the antioxidant mixture failed to significantly affect plasma CRP levels, in contrast to two of three previous studies that did find an effect, may be accounted for by dose and/or interaction of constituent antioxidants. As shown in Table 4, CRP lowering has been reported at higher doses of vitamin E (800 IU, 1200 IU) in type II diabetics and healthy individuals [21,22], but not at lower doses among healthy individuals [27].

We had hypothesized that the antioxidant mixture including vitamin E would produce a larger effect on CRP than would vitamin C alone, and this hypothesis was not confirmed. The hypothesis was based on prior vitamin E studies [21,22], on research showing that {alpha}-tocopherol inhibits pro-inflammatory cytokine release via inhibition of the 5-lipoxygenase pathway [28–30], and that vitamin C may spare or regenerate {alpha}-tocopherol. Instead, the antioxidant mixture produced only a modest 4.7% reduction in CRP. These findings do not appear to be attributable to bias resulting from differential subject selection or protocol adherence. Subjects were randomly assigned to treatment groups, the numbers of subjects eliminated from the data because of plasma CRP levels below the assay’s limit of detection, or because of clinical elevations, were similar between groups, and the resulting groups were similar with respect to known confounding variables. Further, there was no apparent evidence of differential effects related to dietary habits, exposure to cigarette smoke, or capsule consumption between treatment groups.

The fact that the CRP-lowering effect observed in the vitamin C group was not repeated in the group taking the antioxidant mixture that included vitamin C raises the possibility that the observed effect was a chance finding or that the constituent antioxidants interacted to blunt the overall CRP response to vitamin C. The only report of administration of vitamins C and E, in a mixture similar to ours, is found in the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) clinical trial [31] that produced results much like ours. A combination of vitamin C (500 mg/d) and vitamin E (272 IU/d) over 3 yrs in healthy men failed to reduce plasma CRP, TNF-{alpha}, or interleukin-6 levels during that period of time (Table 4) [32]. The anti-inflammatory effects of the individual supplements were not examined. The possibility of a negative antioxidant interaction is supported by the finding among high-BMI smokers in our clinical trial, in which vitamin C alone significantly lowered oxidative stress as measured by plasma F2-isoprostane levels, but the antioxidant mixture did not [23].

This study raises a number of questions, and in doing so it underscores the need for further research into the anti-inflammatory effects of dietary antioxidants including (1) confirming the CRP-lowering effects of vitamin C; (2) clarifying the anti-inflammatory dose effects and interactions of dietary antioxidants; (3) identifying disease-specific or risk factor-specific dietary antioxidant combinations appropriate as anti-inflammatory interventions.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 CONCLUSION
ACKNOWLEDGMENTS
 REFERENCES
 
Emerging evidence suggests that plasma CRP may directly affect progression of atherosclerosis [13–19]. Statins have been shown to reduce CRP by 15–25% and reduce coronary event rates among those with lower concentrations of LDL cholesterol and above median levels of CRP [33,34], adding further support for a direct CRP-mediated antiatherogenic effect. The 24.0% CRP-lowering effect of vitamin C supplementation seen in this study is comparable in magnitude to that observed with statin drugs. If our observed results are indicative of a true impact of vitamin C, the magnitude of the public health benefit could be large. These findings suggest the need for follow-up randomized controlled clinical trials with the specific aim to evaluate the impact of dietary antioxidants on plasma CRP and other pro-inflammatory factors among populations at risk for cardiovascular disease.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 CONCLUSION
 ACKNOWLEDGMENTS
REFERENCES
 
Funding/Support: This research was supported by the University of California Tobacco-Related Disease Research Program (TRDRP:6RT-0008 and 7RT-0160), by National Institutes of Health grant P30 ES01896, by National Cancer Institute grant 1RO3 CA 94612-01, and by the German Academic Exchange Service, DAAD, Postdoctoral Fellowship (Dr Dietrich).

Received August 11, 2003. Accepted December 11, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 

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