Effect of cigarette smoking on plasma uric acid concentrations
Environ Health Prev Med
Effect of cigarette smoking on plasma uric acid concentrations
Dhouha Haj Mouhamed 0 1
Asma Ezzaher 0 1
Fadoua Neffati 0 1
Wahiba Douki 0 1
Lotfi Gaha 0 1
Mohamed Fadhel Najjar 0 1
W. Douki 0 1
0 L. Gaha Psychiatry Department, University Hospital of Monastir , 5000 Monastir , Tunisia
1 D. Haj Mouhamed (&) A. Ezzaher F. Neffati M. F. Najjar Laboratory of Biochemistry-Toxicology, University Hospital of Monastir , 5000 Monastir , Tunisia
Objectives The purpose of this study was to examine the effect of cigarette smoking on plasma uric acid concentration and to determine the correlation between this parameter and the biological tobacco markers, plasma thiocyanate and urinary cotinine. Methods The initial study was conducted on 300 subjects; 138 of them were nonsmokers (62 men and 76 women) aged 14-72 years and 162 were current smokers (145 men and 17 women) aged 16-85 years. Uric acid, creatinine, and urinary cotinine were determined by the enzymatic colorimetric method and plasma thiocyanate by selective electrode. Results Plasma uric acid concentration was significantly lower in smokers than in nonsmokers. A statistically significant negative correlation was noted between the smoking status parameters, including both the number of cigarettes smoked/day (F3-161 = 12.063; r = -0.9968; p = 0.0001) and the duration of smoking (F3-161 = 1.305; r = -0.9406; p = 0.0274), and the plasma uric acid. Among smokers, we noted a negative correlation between uric acid and both plasma thiocyanates (r = -0.437; p \ 0.05) and urinary cotinine (r = -0.580; p \ 0.05). Conclusion After excluding the other factors affecting the uric acid levels, the significant low plasma uric acid in smokers was attributed to a reduction of the endogenous production as a result of the chronic exposure to cigarette smoke that is a significant source of oxidative stress. Therefore, it is recommended to stop or reduce smoking and to introduce plasma uric acid estimation as a routine test, since it is cheap and simple to reflect the antioxidant level.
thiocyanate; Cigarette smoking; Urinary cotinine; Plasma; Uric acid; Oxidative stress
Cigarette smoking is known to contribute to many diseases,
including cancer, chronic obstructive pulmonary disease,
stroke, cardiovascular diseases, and peptic ulcers [
Investigators have attempted to elucidate the mechanisms
of the pathogenesis associated with cigarette smoking, but
the conclusions were not consistent. A basic hypothesis is
that free radicals cause oxidative damage to
macromolecules such as lipids, proteins, and DNA. Therefore, these
radicals play an important role in the pathogenesis of
diseases . In accordance with this theory, antioxidants are
believed to play important roles in resisting damage from
oxidative stress resulting from cigarette smoking. Several
studies were conducted concerning the relationship
between smoking and antioxidants, focusing on the
differences of the effect of antioxidants between smokers and
nonsmokers. However, the results were controversial.
As cigarette smoke contains superoxide and reactive
nitrogen species that readily react with various
biomolecules, it has been hypothesized that some of the adverse
effects of smoking may result from the oxidative damage to
the endothelial cells, which results in nitric oxide
deficiency. Nitric oxide regulates the vascular tone and its
deficiency accelerates the insufficiency of the coronary
artery and vasoconstriction in different tissues. Therefore,
the imbalance between oxidants and antioxidants may play
an important role in the smoker [
]. In addition, cigarette
smokers have increased inflammatory responses that
further enhance their oxidative stress; in humans, uric acid is
the most abundant aqueous antioxidant, accounting for up
to 60% of serum free radical scavenging capacity, and it is
an important intracellular free radical scavenger during
metabolic stress, including smoking [
measurement of its serum level, therefore, reflects the antioxidant
capacity . Nicotine is the main substance that results in
addiction to smoking. Because nicotine is a substance
specific to cigarette smoking, it can be used as a marker for
the number of cigarettes consumed [
]. Therefore, it allows
to quantify the amount that a subject smokes. Nicotine
metabolites, including cotinine, nicotine-N-oxide, and a
number of derivatives, offer a priority consideration. These
are more accurate than other biomarkers such as
carboxyhemoglobin or carbon monoxide, which are not predictors
of the number of cigarettes smoked. In addition, such
biomarkers may be present as a result of exposure to other
environmental factors [
The aim of this study was to demonstrate the possible
effect of smoking on plasma uric acid concentration and to
determine the correlation between this parameter and the
biological tobacco markers, plasma thiocyanate and urinary
Materials and methods
The initial study was conducted on 300 voluntary subjects;
138 of them were nonsmokers (62 men and 76 women)
aged 35.6 ± 16.0 years and 162 were current smokers (145
men and 17 women) aged 38.0 ± 17.5 years. This study
had been approved by the local ethical committee. Written
informed consent was obtained from all voluntary adult
participants and from the parents of minors.
they were required for analysis. All of the samples were
analyzed for urinary cotinine.
Subject information and cigarette smoking outcome data
were collected in a structured interview. The available data
were limited to the classification of smoking to three
categories: never, former, or current. The majority of current
and former smokers were able to provide information on
the number of cigarettes they smoked and the duration of
smoking. All subjects were questioned concerning their
medical history and sociodemographic characteristics,
including age, gender, education, and employment.
Uric acid, creatinine, and urinary cotinine levels were
determined by the enzymatic colorimetric method on the
Konelab 30TM analyzer (Thermo Electron Corporation).
Cotinine was expressed as micrograms per micromol of
creatinine in urine. SCN- levels were determined using
selective electrodes (Ionometer SevenMulti S80TM, Mettler
Toledo, Schwerzenbach, Switzerland) and expressed as
milligrams per liter in plasma.
The results were expressed as means ± standard deviation
(SD). Standard descriptive statistics, correlation
coefficients, and significance tests were calculated using the
SPSS 17.0 program. Differences between mean values
were evaluated by Student’s t-test and between frequency
values by the v2 test. Comparisons between smokers and
nonsmokers in uric acid levels were applied by analysis of
variance (ANOVA) after adjustment to potential
confounders’ factors (factors of arthrosclerosis such as
cholesterol, high-density lipoproteins [HDL] and low-density
lipoproteins (LDL), alcohol drinking, creatinine, and body
mass index [BMI]). A p-value of less than 0.05 was
considered to represent a statistically significant difference
For plasma uric acid, creatinine, and thiocyanates, venous
blood was drawn in tubes containing lithium heparinate
and it was immediately centrifuged. The plasma samples
were stored at -20 C until analysis. Urine samples were
obtained from the smokers and nonsmokers. These samples
were either used on the same day or frozen at -20 C until
We noted that plasma uric acid was significantly lower in
smokers than in nonsmokers (p = 0.0003, Table 1). It was
also significantly lower in smoking men than nonsmoking
men (203 ± 100 vs. 337 ± 100; p \ 10-7). The same
result was found for women (171 ± 72 vs. 223 ± 130;
p = 0.02) (Fig. 1).
After adjustment of plasma uric acid levels to
confounders’ factors, we noted a significant difference
between smokers and nonsmokers (p \ 0.0001).
Table 1 clearly shows that smokers have lower plasma
urea levels than nonsmokers. We found a significant
dissimilarity between smokers and nonsmokers in the urinary
cotinine (p \ 10-7) and plasma SCN- levels (p \ 0.0005).
In this study, we found a significant difference between
subjects smoking more than 20 cigarettes/day and those
smoking less than 20 cigarettes/day (v2 = 22.4; p \ 10-7).
We noted a significant decrease of uric acid concentration
when the smoking duration exceeds 5 years (v2 = 3.89;
p = 0.04) (Table 2).
The number of cigarettes smoked/day was significantly
higher in subjects having uric acid values below 200 lmol/
L than in others (24 ± 9.58 vs. 19 ± 9.55 cigarettes/day;
p = 0.01).
A statistically significant negative correlation was noted
between the smoking status parameters, including both the
number of cigarettes smoked/day (F3–161 = 12.063; r =
-0.9968; p \ 0.05; Fig. 2a) and the duration of smoking
Many, but not all, epidemiological studies have suggested
that high plasma uric acid is a risk factor for cardiovascular
diseases, and they aimed at evaluating its prognostic
implications and potential utility in the therapy monitoring
]. This raised level of plasma uric acid, parallel to an
increased risk of cardiovascular diseases, could be either
primary or secondary to the underlying causes of the
cardiovascular diseases . However, the specific role of
plasma uric acid in this constellation remains uncertain,
although it may be involved in the platelet adhesiveness,
aggregation, or inflammation, and it may be implicated in
the genesis of hypertension [
]. In contrast, there is some
evidence that the increase of plasma uric acid is protective
against the cardiovascular diseases, since uric acid acts as
an endogenous antioxidant [
], and the higher plasma
uric acid levels found in cardiovascular diseases patients
suggest that any protective antioxidant effect of uric acid is
hidden by other negative effects in these pathogeneses.
In this study, the plasma uric acid level in smokers was
significantly lower than in nonsmokers (p = 0.0003), both
in men (p \ 10-7) and in women (p = 0.02). This could
confirm the effect of cigarette smoking on uric acid levels
independently of the gender. In addition, we noted a
significant negative correlation with the smoking status,
including the average number of cigarettes smoked/day and
the smoking duration. Moreover, we noted that the uric
acid levels decrease when the smoking duration exceeds
5 years. This finding is in agreement with other studies
showing a low plasma uric acid in regular smokers [
a reduction of antioxidants, including uric acid, in smokers,
indicating that oxidative stress increases each time a
cigarette is smoked [
]. Other studies proved that even
nonsmokers exposed to cigarette smoke have a
significantly lower plasma antioxidant status than unexposed
nonsmokers, independently of the differences in the dietary
antioxidant intake . Others studies proved that the
administration of uric acid increases the circulating
antioxidant defenses and allows the restoration of
endothelium-dependent vasodilatation [
]. A decrease of uric acid
in smokers can be explained by the inactivation of xanthine
oxidase by cyanide, which is eliminated as thiocyanate
]. Therefore, high plasma uric acid concentrations
might be protective in situations characterized by an
increase of cardiovascular risk and oxidative stress, such as
smoking , and a reduction of its level, which increases
susceptibility to oxidative damage and accounts for the
excessive free radical production [
]. Therefore, the
possibility that uric acid confers protection against the
development of atherosclerosis, in view of its antioxidant
properties, has been recognized [
In this study, we found a significant decrease of plasma
creatinine levels in smokers compared to nonsmokers,
although these values are not pathological. This can confirm
that all of the subjects studied are without any renal failure,
since the determination of creatinine has been reported to be
useful in evaluating the renal handling of uric acid and as
concentrations of this parameter are highly dependent on
endogenous production as well as on renal excretion [
]. Therefore, the low plasma uric acid level in smokers is
attributed to a reduction of endogenous production.
This finding is in agreement with other studies that
proved that the reduction of antioxidants, including uric
acid in smokers, is due to both the chronic exposure to
cigarette smoke, which is a significant source of oxidative
stress, and to the low intake of dietary antioxidants [
Some of the relationships between tobacco and urea or
uric acid are very significant; however, they are all very
weak. If these relationships have the same origin, a
hypothetical renal mechanism must first be considered. In fact,
the blood urea is a product of the catabolism of proteins
and their amino acids, whereas uric acid originates from
the oxidation of purines. Moreover, the two molecules,
while circulating in the blood, remain unlinked, either
directly or by a common carrier. On the contrary, they are
both excreted by the kidney, and in the disease processes,
they generally vary in the same way: a rise in blood uric
acid is well known as an early sign of renal failure. An
increase in the renal excretion of urea and uric acid under
the influence of tobacco is, therefore, a reasonable
hypothesis, and it is supported by the known action of
nicotine on the metabolism of catecholamines and the
effect of these substances on renal function [
Urinary cotinine and plasma SCN- concentrations were
both significantly higher in smokers than in nonsmokers,
and they were well correlated with the number of cigarettes
smoked per day and with the duration of consumption.
Although cotinine and plasma SCN- are influenced by diet
and industrial pollution, it remains a reliable indicator of
the smoking status [
We found a negative correlation between the plasma
uric acid level and both urinary cotinine concentration
(r = -0.580) and plasma SCN- concentration (r =
-0.437) in active smokers. The important correlation
found between urinary cotinine and plasma uric acid in
smokers was not surprising because the urinary cotinine
and plasma SCN- levels were determined as a marker of
tobacco smoke exposure [
In our study, plasma antioxidant levels were closely, but
inversely, related to the levels of plasma nicotine
metabolites. It can be explained that more regular cigarette
smoking will markedly affect plasma nicotine metabolites,
and, thus, decrease plasma antioxidant levels. Furthermore,
our finding suggests that plasma nicotine metabolites are
appropriate as biomarkers for smoking consumption. These
biomarkers should be applied in future studies on cigarette
Several methodological limitations should be considered
when interpreting these findings. First, larger sample sizes
of the groups would be beneficial. Second, our work is a
cross-sectional study that does not permit to follow up
biological parameters. Finally, the sample of smokers may
not be representative of more heterogeneous populations.
After the exclusion of other factors affecting uric acid
levels, the significant low plasma uric acid level in smokers
was attributed to a reduction of endogenous production as a
result of the chronic exposure to cigarette smoke that is a
significant source of oxidative stress. Therefore, cigarette
smoking may influence oxidative stress by affecting the
levels of plasma antioxidants, which may be involved in
the mechanisms underlying various diseases. As this
reduction is proportionate with the smoking status and
leads to cardiovascular diseases, it is recommended to stop
or reduce smoking and to introduce plasma uric acid
estimation as a routine test, since it is cheap and simple to
reflect the antioxidant status.
Acknowledgments The authors thank Mr. Samir Boukattaya for his
assistance with the English language corrections.
Conflict of interest The authors stated that there are no conflicts of
interest regarding the publication of this article.
1. Leistikow BN , Tsodikov A . Cancer death epidemics in United States Black males: evaluating courses, causation, and cures . Prev Med . 2005 ; 41 : 380 - 5 .
2. Mallampalli A , Guntupalli KK . Smoking and systemic disease . Clin Occup Environ Med . 2006 ; 5 : 173 - 92 .
3. Chiu YW , Chuang HY , Huang MC , Wu MT , Liu HW , Huang CT . Comparison of plasma antioxidant levels and related metabolic parameters between smokers and non-smokers . Kaohsiung J Med Sci . 2009 ; 25 : 423 - 30 .
4. van der Vaart H , Postma DS , Timens W , ten Hacken NHT. Acute effects of cigarette smoke on inflammation and oxidative stress: a review . Thorax . 2004 ; 59 : 713 - 21 .
5. Mathru M , Dries DJ , Barnes L , Tonino P , Sukhani R , Rooney MW . Tourniquet-induced exsanguination in patients requiring lower limb surgery. An ischemia-reperfusion model of oxidant and antioxidant metabolism . Anesthesiology . 1996 ; 84 : 14 - 22 .
6. Hellsten Y , Tullson PC , Richter EA , Bangsbo J . Oxidation of urate in human skeletal muscle during exercise . Free Radic Biol Med . 1997 ; 22 : 169 - 74 .
7. Maxwell SR , Thomason H , Sandler D , LeGuen C , Baxter MA , Thorpe GH , et al. Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus . Eur J Clin Invest . 1997 ; 27 : 484 - 90 .
8. Leone A . Biochemical markers of cardiovascular damage from tobacco smoke . Curr Pharm Des . 2005 ; 11 : 2199 - 208 .
9. Meisinger C , Koenig W , Baumert J , Do ¨ring A. Uric acid levels are associated with all-cause and cardiovascular disease mortality independent of systemic inflammation in men from the general population: the MONICA/KORA cohort study . Arterioscler Thromb Vasc Biol . 2008 ; 28 : 1186 - 92 .
10. Ioachimescu AG , Brennan DM , Hoar BM , Hazen SL , Hoogwerf BJ . Serum uric acid is an independent predictor of all-cause mortality in patients at high risk of cardiovascular disease: a preventive cardiology information system (PreCIS) database cohort study . Arthritis Rheum . 2008 ; 58 : 623 - 30 .
11. Kawamoto R , Tomita H , Oka Y , Ohtsuka N . Relationship between serum uric acid concentration, metabolic syndrome and carotid atherosclerosis . Intern Med . 2006 ; 45 : 605 - 14 .
12. Waring WS , Webb DJ , Maxwell SR . Systemic uric acid administration increases serum antioxidant capacity in healthy volunteers . J Cardiovasc Pharmacol . 2001 ; 38 : 365 - 71 .
13. Schretlen DJ , Inscore AB , Jinnah HA , Rao V , Gordon B , Pearlson GD . Serum uric acid and cognitive function in communitydwelling older adults . Neuropsychology . 2007 ; 21 : 136 - 40 .
14. Waring WS , Convery A , Mishra V , Shenkin A , Webb DJ , Maxwell SR . Uric acid reduces exercise-induced oxidative stress in healthy adults . Clin Sci . 2003 ; 105 : 425 - 30 .
15. Tsuchiya M , Asada A , Kasahara E , Sato EF , Shindo M , Inoue M. Smoking a single cigarette rapidly reduces combined concentrations of nitrate and nitrite and concentrations of antioxidants in plasma . Circulation . 2002 ; 105 : 1155 - 7 .
16. Dietrich M , Block G , Norkus EP , Hudes M , Traber MG , Cross CE , et al. Smoking and exposure to environmental tobacco smoke decrease some plasma antioxidants and increase gammatocopherol in vivo after adjustment for dietary antioxidant intakes . Am J Clin Nutr . 2003 ; 77 : 160 - 6 .
17. Waring WS , McKnight JA , Webb DJ , Maxwell SRJ . Uric acid restores endothelial function in patients with type 1 diabetes and regular smokers . Diabetes . 2006 ; 55 : 3127 - 32 .
18. Massey V , Edmondson D . On the mechanism of inactivation of xanthine oxidase by cyanide . J Biol Chem . 1970 ; 245 : 6595 - 8 .
19. Puig JG , Mateos FA , Jime´nez ML, Ramos TH . Renal excretion of hypoxanthine and xanthine in primary gout . Am J Med . 1988 ; 85 : 533 - 7 .
20. Leyva F , Wingrove CS , Godsland IF , Stevenson JC . The glycolytic pathway to coronary heart disease: a hypothesis . Metabolism . 1998 ; 47 : 657 - 62 .
21. Bloomer RJ . Decreased blood antioxidant capacity and increased lipid peroxidation in young cigarette smokers compared to nonsmokers: impact of dietary intake . Nutr J. 2007 ; 6 : 39 - 40 .
22. Watts DT . The effect of nicotine and smoking on the secretion of epinephrine . Ann N Y Acad Sci . 1960 ; 90 : 74 - 90 .
23. Bruckert E , Jacob N , Lamaire L , Truffert J , Percheron F , de Gennes JL. Relationship between smoking status and serum lipids in a hyperlipidemic population and analysis of possible confounding factors . Clin Chem . 1992 ; 38 : 1698 - 705 .
24. Haj Mouhamed D , Ezzaher A , Neffati F , Douki W , Najjar MF . Comparison between plasma and urine thiocyanates and urinary cotinine determinations as indicators of cigarette smoking . J Health Sci . 2009 ; 55 : 1 - 6 .