Racial Differences in Exposure and Glucuronidation of
the Tobacco-Specific Carcinogen 4-
Joshua E. Muscat, Ph.D., M.P.H.1
Mirjana V. Djordjevic, Ph.D.2
Stephen Colosimo, M.S.3
Steven D. Stellman, Ph.D., M.P.H.4
John P. Richie, Jr, Ph.D.1
1Department of Health Evaluation Sciences, Penn-
sylvania State Cancer Institute, Pennsylvania State
College of Medicine, Hershey, PA.
2Tobacco Control Research Branch, National Can-
cer Institute, National Institutes of Health, Be-
3Institute for Cancer Prevention, Valhalla, NY.
4Department of Epidemiology, Mailman School of
Public Health, Columbia University, New York, NY.
Supported by USPHS Grants P01-CA-68384, and
Address for reprints: Joshua E. Muscat, Pennsyl-
vania State Cancer Institute, Division of Population
Sciences, Department of Health Evaluation Sci-
ences, Pennsylvania State University College of
Medicine, Rm. C3739C, MC-H078, 500 University
Drive, Hershey, PA 17033. Fax: (717) 531-0480.
Received August 26, 2004; revised December 15,
2004; accepted December 15, 2004.
BACKGROUND: In the United States, Blacks who smoke cigarettes have a higher
mean blood concentration of the nicotine metabolite cotinine than White smokers.
It has not been determined whether there are racial differences in the exposure to
the cigarette smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK) and in the detoxification of NNK metabolites.
METHODS: A community-based cross-sectional survey of 69 Black and 93 White
smokers was conducted in lower Westchester County, New York. Information on
smoking and lifestyle habits was collected and urinary concentrations of several
tobacco smoke biomarkers were compared, including the NNK metabolite
(NNAL-Gluc). A frequency histogram and probit plot of NNAL-Gluc:NNAL ratios
were constructed to determine slow and rapid glucuronidation phenotypes.
RESULTS: The mean concentrations of total NNAL, urinary cotinine, plasma coti-
nine, and thiocyanate were significantly higher in Black men than in White men for
each cigarette smoked. In women, the only biomarker that was significantly ele-
vated in Blacks was plasma cotinine. A higher proportion of White versus Black
women was categorized as “rapid” glucuronidators (two-tailed exact test, P ? 0.03).
In men, there were no significant differences in NNAL-Gluc:NNAL phenotypes.
CONCLUSIONS: The higher rates of lung carcinoma in black men may be due in part
to a higher level of exposure to tobacco smoke carcinogens. Cancer 2005;103:
1420–6. © 2005 American Cancer Society.
imately 40–50% higher in Black men than in White men since 1973.1
This large difference does not appear to be entirely due to adult
smoking prevalence, which was similar for Whites and Blacks up until
1960. By 1970, the prevalence rates had diverged to about 55% in
Black men and 45% in White men but had declined to 23% in both
groups by 2002.2,3The proportion of Black and White women who
smoke has been similar for several decades. Black men and women
start smoking at a later age and smoke fewer cigarettes per day than
White men and women, respectively.4–6Consequently, the similar or
higher rates of lung carcinoma in Blacks may be explained by expo-
sure to a higher dose of cigarette compounds during inhalation. In
serologic studies, the mean cotinine concentrations are higher in
Blacks than Whites for each cigarette smoked.9–12Cotinine is a me-
tabolite of the addicting agent nicotine and is considered a sensitive
indicator of exposure to numerous toxic compounds in tobacco
smoke. One possible way to test whether there is a differential effect
of smoking between Blacks and Whites is to compare lung carcinoma
(NNAL) andits glucuronide
he annual incidence rate of lung carcinoma in the Surveillance,
Epidemiology, and End Results (SEER) program has been approx-
© 2005 American Cancer Society
Published online 22 February 2005 in Wiley InterScience (www.interscience.wiley.com).
rates in smokers, but SEER and other cancer registries
do not collect information on individual smoking hab-
its. Two case-control studies found a higher risk of
smoking-associated lung carcinoma in Black men
than in White men but similar risks between Black and
To determine if there are differences in exposure
to tobacco smoke carcinogens between Blacks and
Whites, the authors of the current study measured the
urinary metabolites of the carcinogen 4-(methylnitro-
samino)-1-(3-pyridyl)-1-butanone (NNK), which is
found only in tobacco smoke (Figure 1). The uptake of
NNK can be quantified by measurement of both uri-
(NNAL) and its glucuronides (NNAL-N-Gluc and
NNAL-O-Gluc; collectively NNAL-Gluc).13NNAL is
formed by carbonyl reduction of NNK, and like NNK,
NNAL induces lung adenocarcinoma in rodents. It is
considered a likely cause of human lung carcinoma
and a specific biomarker for tobacco smoke carcino-
genicity.14–18Both NNK and NNAL are metabolically
activated by hydroxylation, leading to formation of
DNA adducts. Chemopreventive agents such as iso-
thiocyanates inhibit P450 enzyme activation of NNK
in rats, resulting in decreased adduct formation. The
increase in human lung adenocarcinoma incidence
rates over the past few decades is associated with
increasing levels of nitrosamines in cigarettes.19
NNAL is conjugated to its presumed detoxified
ferases (UGTs). Cotinine is also conjugated by UGTs to
form polar compounds. In pharmacokinetic studies,
the rate of UGT-mediated glucuronidation of cotinine
was significantly lower in Blacks.20Pharmacokinetic
studies of NNAL glucuronidation in Blacks and Whites
would be useful to determine possible differences in
NNAL detoxification rates. These have not yet been
reported, but the authors of the current study previ-
ously showed in preliminary data on 61 subjects that
the mean ratio of NNAL-Gluc:NNAL, a marker of NNK
detoxification, was lower in Blacks than in Whites.10
The current report updates these findings and com-
pares differences in the exposure and metabolism of
NNK between Blacks and Whites.
MATERIALS AND METHODS
In addition to the first 61 participants that were re-
cruited during 1994–1996, the authors of the current
study enrolled an additional 101 participants during
1996–2000, yielding a total sample of 162. All 162
subjects were non-Hispanic Black and White smokers
ages 20–50 years who lived or worked in the Yonkers
or Mount Vernon areas of lower Westchester County,
New York. These subjects smoked at least 5 cigarettes
a day for ?1 years and did not use other tobacco
products. Recruitment methods included distribution
of fliers, newspaper advertisements, online announce-
ments, word of mouth, and recommendations from
community leaders. All subjects received remunera-
tion and transportation fees, and signed a consent
form that was approved by the Institutional Review
Board of the Institute for Cancer Prevention. Trained
interviewers administered a structured questionnaire
that contained items on cigarette smoking history,
including cigarette brands, cigarettes smoked each
day (cpd), age at smoking onset, and total years of
FIGURE 1. Schematic of NNK metabolism.
Racial Differences in Tobacco Smoke Exposure/Muscat et al.1421
Analysis of Tobacco Biomarkers
Authors of the current study collected urine samples
in the morning and stored the aliquots at ?20 °C.
Blood specimens were collected into tubes containing
EDTA anticoagulant and immediately placed on ice.
Within 4 hours, the blood was centrifuged at 2,100
? gravity for 15 minutes at a temperature of 4 °C. The
plasma was separated, removed, placed into aliquots,
and frozen at ?20 °C. Gas chromatography-thermal
energy analyzer (GC-TEA) was used to measure uri-
nary NNAL, NNAL-Gluc, and total NNAL.13Enzyme-
Linked Immunosorbent Assay (ELISA) (OraSure Tech-
nologies Inc., Bethlehem, PA) was performed to
quantify levels of urinary and plasma cotinine. A
Vitros Ektachem 500 (Ortho Clinical Diagnostics of
Johnson & Johnson, Rochester, NY) clinical chemistry
analyzer was used to measure urinary creatinine lev-
els. Plasma thiocyanate (TCN), which is derived from
hydrogen cyanide in the gas phase of tobacco smoke,
was measured spectrophotometrically.21
Statistical analyses were conducted using SAS soft-
ware (SAS Inc., Cary, NC). Concentrations of the uri-
nary metabolites were expressed in grams of creati-
nine to correct for variation in urine flow. Student t
and chi square tests were conducted to compare
smoking and other questionnaire data between Blacks
and Whites. The validity of self-reported smoking in-
formation was tested for 133 subjects by comparing
the number of cigarette butts they stored in a plastic
container over a 4-day period with their self-reported
smoking habits. The Pearson correlation coefficient
was 0.95 in Blacks and 0.83 in Whites.
Cotinine and TCN measurements were normally
distributed. NNAL values were log-transformed and
described using geometric means. For determining
racial differences in smoking exposure, generalized
linear regression models were used to predict levels of
cotinine, TCN, NNAL, NNAL-Gluc, total NNAL (NNAL
? NNAL-Gluc), and NNAL-Gluc:NNAL. The models
were fitted using cpd as the main effect variable and
age adjusted (continuous). A quadratic term for cpd
was used to test a departure from linearity. Racial
differences in cigarette metabolite levels were tested
using a categoric term in separate models for men and
women. All models were tested for an interaction be-
tween cpd and race. Partial F tests were conducted to
determine the best predictive models. If the final
model included an interaction term, the mean level of
the tobacco metabolite was described for light smok-
ers (?20 cpd) and heavy smokers (?20 cpd) sepa-
A frequency histogram and a probit plot were
analyzed to determine the critical values used to esti-
mate glucuronidation phenotypes. In a preliminary
analysis of 61 smokers, the data showed two distinct
phenotypes at ratios of ?6.0 (“slow” glucuronidators)
and ?6.0 (“rapid” glucuronidators). A two-tailed
Fisher exact test was calculated to determine the prob-
ability value for proportional differences in NNAL
phenotypes between Blacks and Whites.
Black and White subjects had similar ages, years of
education, marital status, and occupational category
(e.g., clerical, sales, technical, and professional or
managerial). The average age of participants was 35
years for Black men, 34 years for White men, 36 years
for Black women, and 32 years for White women.
Approximately 69% of both Blacks and Whites had
more than a high school education.
Cigarette Characteristics by Race And Sex
The mean age of smoking onset was about 15.5–17.0
years in all groups, and the average number of years
smoked was 15–19 (Table 1). The percentage of sub-
jects who smoked 10 or more cpd was 87%. The mean
number of cigarettes smoked was approximately 17 in
Black men, 24 in White men, 14 in Black women, and
22 in White women. Nearly all subjects smoked filter
cigarettes. In men, 29% of Blacks and 13% of Whites
smoked filter cigarettes with long tobacco rods (?100
mm). Blacks smoked predominantly menthol ciga-
rettes, which have higher average Federal Trade Com-
mission (FTC) nicotine and tar yields (Table 1). The
percentage of menthol smokers was 78.6% in Black
men, 17.4% in White men, 82.5% in Black women, and
15.2% in White women. Because Blacks smoked fewer
cigarettes per day, the total daily FTC nicotine expo-
sure did not differ significantly between Black and
White men. The daily intake of nicotine was lower in
Black women than in White women (P ? 0.01).
Urinary and Blood Concentrations of Cigarette Smoke
The R2for all models is shown in Table 2. The number
of cigarettes smoked each day explained the largest
source of variation in the regression models. In men
the R2ranged from 0.21 to 0.37. The geometric mean
levels of urinary NNAL-Gluc pmol/mg creatinine were
1.9 in Black men and 1.4 in White men (P ? 0.01).
Black men also had significantly higher levels of total
NNAL. The mean levels of urinary cotinine were 5.6
?g/mg creatinine in Black men and 3.2 ?g/mg creat-
inine in White men (P ? 0.01). The corresponding
1422CANCER April 1, 2005 / Volume 103 / Number 7
values for plasma cotinine (ng/ml) were 5.6 and 3.2 (P
? 0.02). The model that best predicted plasma levels
of TCN in men included a significant interaction term
for race and cpd. In light smokers (?20 cpd), the mean
concentration of TCN was similar for Blacks and
Whites. In heavy smokers, Blacks had higher TCN
concentrations than Whites. In women, the models
explained only a small amount of variation in the
biomarker levels, except plasma cotinine (Table 2).
There were no significant differences in urinary NNAL,
NNAL-Gluc, total NNAL , cotinine, and plasma TCN
levels between Blacks and Whites. Only plasma coti-
nine levels were higher in Blacks than in Whites (450
vs. 274 ng/ml; P ? 0.01).
The frequency distribution of NNAL-Gluc:NNAL
ratios is shown in Figure 2. There were no significant
racial differences in the mean ratio of NNAL-Gluc:
NNAL in men, whereas the mean ratio of NNAL-Gluc:
NNAL was higher in White women than in Black
women (P ? 0.01; Table 3). In women, there was a
clear cutpoint at a ratio of 6.0, which was confirmed by
visual examination of sex-specific histograms (Figure
3). All women except one with ratios of ?6 were White.
In Black women, 40 of 41 subjects had ratios of ?6.0 (P
? 0.03; Table 3). In men, the frequency distribution
(Figure 3) did not show evidence of two distinct phe-
notypes. There were no significant differences in the
proportion of Black and White men with NNAL-Gluc:
NNAL ratio values of ?6 (Table 3).
Authors of the current study previously reported
Cigarette Smoking History and Cigarette Characteristics by Race and Sex
(n ? 28)
(n ? 47)
(n ? 41)
(n ? 46)
Mean FTC nicotine
Mean FTC tar content
Cigarette size (%)
15.5 ? 2.4
16.7 ? 8.9
18.7 ? 8.3
16.0 ? 3.5
23.7 ? 11.9
17.8 ? 10.9
17.0 ? 5.4
14.0 ? 7.9
17.8 ? 7.6
16.0 ? 4.1
22.0 ? 10.3
15.2 ? 9.6
1.2 ? 0.15
19.9 ? 11.2
1.0 ? 0.27
24.4 ? 13.4
1.2 ? 0.22
17.1 ? 11.2
0.87 ? 0.25
20.1 ? 12.8
15.9 ? 1.9
268 ? 150
13.2 ? 4.0
320 ? 198
15.6 ? 3.0
223 ? 144
10.8 ? 3.7
251 ? 171
CPD: cigarettes each day; FTC: Federal Trade Commission; NS Not significant.
Multivariate Adjusted Geometric Mean Levels of NNK Metabolites and Arithmetic Mean Levels of Cotinine and Thiocyanate by Race and Sex
Blacks WhitesP value Blacks WhitesP value
NNAL (pmol/mg creat.)
NNAL-Gluc (pmol/mg creat.)
Total NNAL (pmol/mg creat.)
Cotinine (?g/mg creat.)
CPD: cigarettes per day.
P values are adjusted for age and cigarettes each day.
Racial Differences in Tobacco Smoke Exposure/Muscat et al.1423
that NNAL-Gluc:NNAL ratios exhibited two distinct
phenotypes in 61 subjects based on the same cut-
points. Authors of the current study examined the
sex-specific NNAL-Gluc:NNAL means and phenotypes
for these 61 subjects. Similar to the entire study sam-
ple, the mean ratio was 22% higher in White men (n
? 14) than in Black men (n ? 15), although the dif-
ferences were not significant. The mean ratio was 74%
higher in White women (n ? 11) than in Black women
(n ? 21) (P ? 0.05).
The hypothesis that Blacks are exposed to higher lev-
els of tobacco smoke carcinogens was based in part on
their relatively high blood cotinine levels,9–12which
was confirmed in the current investigation. The levels
of blood cotinine also reflect the intake of nicotine,
which needs to be taken into account when explaining
exposure differences. Blacks prefer mentholated ciga-
rettes, which have longer rods and higher FTC nico-
tine yields than nonmentholated brands. However,
Blacks smoke fewer cigarettes each day and have
lower daily nicotine intake than Whites (Table 1). The
levels of cotinine in blood also depend on renal and
nonrenal clearance of cotinine. In pharmacokinetic
studies, rates of total and nonrenal cotinine clearance
were lower in Blacks than in Whites.22It is uncertain
whether the clearance rates fully explain racial differ-
ences in blood cotinine, consequently the measure-
ment of other/multiple tobacco smoke biomarkers
were needed in the current study to test whether there
are exposure differences.
The current study finding of substantially elevated
urinary cotinine levels in Black men, despite their
lower clearance, is consistent with differences in ex-
posure. In addition, although there were few Black
men who were heavy smokers, these subjects had
higher levels of TCN than White heavy smokers. TCN
is a sensitive marker of tobacco smoke exposure in
heavy smokers because of its long half life.23In light
smokers, TCN is a less sensitive marker, because it is
abundant in foods such as broccoli, almonds, beer,
and cauliflower.23,24Our finding of higher levels of
NNK metabolites in Blacks supports not only smoke
exposure differences but also provide direct evidence
of carcinogen exposure differences. The metabolites
FIGURE 2. Probit analysis of urinary NNAL-Gluc:NNAL ratios.
Racial Differences in NNAL-Glucuronidation Phenotypes
Geometric mean NNAL-Gluc:NNAL levels were 3.5 in black men, 3.6 in white men, 2.7 in black women,
and 4.1 in white women. Differences in women: P ? 0.01.
<=2 2.1--4.0 4.1--6.0 >6
<=22.1--4.0 4.1--6.0 >6
FIGURE 3. Frequency distribution of urinary NNAL-Gluc:NNAL ratio in men
(upper chart) and women (lower chart).
1424CANCER April 1, 2005 / Volume 103 / Number 7
NNAL and NNAL-Gluc are present only in tobacco
smoke and are, by definition, highly sensitive markers
of exposure to tobacco carcinogen NNK. A recent
study found higher levels of polycyclic aromatic hy-
drocarbon (PAH) DNA adducts in Black smokers than
in White smokers. This finding tends to support the
current study findings, although PAH levels are a less
sensitive indicator of exposure to tobacco smoke be-
cause they also are abundant in the environment and
In women, there appeared to be no differences in
exposure to tobacco smoke between Blacks and
Whites based on similar concentrations of urinary
NNAL, urinary cotinine, and plasma TCN levels. Only
plasma cotinine levels were higher in Blacks, which
may be because of lower cotinine clearance. The cur-
rent study’s preliminary report showed phenotypic
differences in NNAL-glucuronidation, findings that
were confirmed in the final current analysis.10Patients
with a NNAL-Gluc:NNAL ratio above 6.0 were consid-
ered a low-risk phenotype, but significant racial dif-
ferences in NNAL-Gluc:NNAL mean ratios and pheno-
types were found only in women. Of White women,
17% and of Black women, 2.5% were characterized as
rapid glucuronidators. Racial differences in urinary
cotinine and nicotine glucuronidation phenotypes
have also been reported, but not separately, for men
and women.18Authors of the current study cannot
infer at this time that genetic polymorphisms explain
observed phenotypic differences in women. The three
specific UDP-glucuronosyltransferases that glucu-
ronidate NNAL in vitro are UGT1A4, UGT1A9, and
UGT2B7.26Of these, only a polymorphism in the cod-
ing region of the UGT2B7 gene reduces NNAL activi-
ty.27Further, UGT genes are not X-linked, although it
has been reported that there are sex-dependent dif-
ferences in UGT activity.28Several dietary chemopre-
ventive items such as ellagic acid, ferulic acid, Brussels
sprouts, quercetin, garlic, and others induce hepatic
UGT enzyme activity in rats29–31and may affect hu-
man UGT variation as well.
The geometric mean levels of NNAL in the current
study were similar to those reported in other studies of
current smokers,32,33and the findings suggest that
differences in carcinogen exposure or detoxification
may help explain higher rates or risks of lung carci-
noma in Blacks. However, the variation in NNAL levels
was only partly predicted by the linear regression
models in the current study, and the factors that ex-
plain most of the variation in tobacco smoke biomar-
kers have yet to be determined. For example, there
may be differences in the enzymatic reduction of NNK
to NNAL. Only one enzyme, 11-O-hydroxysteroid de-
hydrogenase, has been identified in the reduction of
NNK in mice.34There are no data on human variation
against NNK, but it has been suggested that genetic
variants could play a role.35Differences in environ-
mental smoke exposure might have contributed to the
observed differences. However, studies show that
NNAL levels in ETS-exposed nonsmokers is about 6%
of that in active smokers.36
The high incidence rate of lung carcinoma in
Black men is lowered after making statistical adjust-
ments for socioeconomic status (SES),37which sup-
ports the idea that race is more a social than a biologic
construct in explaining disparities in cancer rates.38
Black men may be at higher risk for lung carcinoma
due to exposure differences that are determined by
smoking behaviors such as puff intensity, puff fre-
quency, and the covering of cigarette filter vents. So-
cial factors associated with low SES in Blacks, such as
stress, may result in increased exposure to cigarette
smoke compared with Whites.39–41Studies are being
conducted to determine whether racial and gender
differences in smoking topography affect tobacco
smoke biomarkers.42These types of studies can lead to
behavioral interventions that reduce the harmful ef-
fects of tobacco smoke in both Blacks and Whites.
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