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).
9. Wagenknecht LE, Cutter GR, Haley NJ, Sidney S, Manolio
TA, Hughes GH, et al. Racial differences in serum cotinine
levels among smokers in the CARDIA Study. Am J Public
10. Richie JP Jr, Carmella SG, Muscat JE, Scott DG, Akerkar SA,
Hecht SS. Differences in the urinary metabolites of the to-
bacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone in black and white smokers. Cancer
Epidemiol Biomark Prev. 1997;6:783–790.
11. Caraballo RS, Giovino GA, Pechacek TF, Mowery PD, Richter
PA, Strauss WJ, et al. Racial and ethnic differences in serum
cotinine levels of cigarette smokers. Third National Health
and Examination Survey, 1988–1991. J Am Med Assoc. 1998;
12. English PB, Eskenazi B, Christianson RE. Black–white differ-
ences in serum cotinine levels among pregnant women and
subsequent effects on infant birthweight. Am J Public
13. Carmella SG, Akerkar SA, Richie JP Jr., Hecht SS. Intraindi-
vidual and interindividual differences in metabolites of the
tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-
(3-pyridyl)-1-butanone (NNK) in smokers’s urine. Cancer
Epidemiol Biomark Prev. 1995;4:635–642.
14. Hecht SS, Hoffmann D. Tobacco-specific nitrosamines, an
important group of carcinogens in tobacco and tobacco
smoke. Carcinogenesis. 1988;9:875–884.
15. Hecht SS. Biochemistry, biology and carcinogenicity of to-
bacco-specific N-nitrosamines. Chem Res Toxicol. 1998;11:
16. Hecht SS. Tobacco smoke carcinogens and lung cancer.
J Natl Cancer Inst. 1999;91:1194–1210.
17. Upadhyaya P, Kenney PMJW M, Hochalter JB, Hecht SS.
Tumorigenicity and metabolism of 4-(methylnitrosamino)-
1-(3-pyridyl)-1-butanol (NNAL) enantiomers and metabo-
lites in the A/J mouse. Carcinogenesis. 1999;20:1577–1585.
18. Hecht SS. Tobacco carcinogens, their biomarkers and tobac-
co-induced cancer. Nat Rev Cancer. 2003;3:733–744.
19. Wynder EL, Muscat JE. The changing epidemiology of smok-
ing and lung cancer histology. Environ Health Perspect.
1995; Nov 103 Suppl 8:143–148.
20. Benowitz NL, Perez-Stable EJ, Fong I, Modin G, Herrera B,
Jacob III P. Ethnic differences in N-glucuronidation of nic-
otine and cotinine. J Pharmacol Exp Ther. 1999;291:1196–
21. Westley J, Thiocyanate and thiosulfate. Methods Enzymol.
22. Perez-Stable EJ, Herrera B, Jacob III P, Benowitz NL. Nico-
tine metabolism and intake in black and white smokers.
J Am Med Assoc. 1998;280:152–156.
23. Jarvis MJ, Tunstall-Pedoe H, Feyerabend C, Vesey C, Sa-
loojee Y. Comparison of tests used to distinguish smokers
from nonsmokers. Am J Public Health. 1987;77:1435–1438.
24. Velicer WF, Prochaska JO, Rossi JS, Snow MG. Assessing
outcome in smoking cessation studies. Psychol Bull. 1992;
25. Weiserbs KF, Jacobson JS, Begg MD, Wang LW, Wang Q,
Agrawal M, et al. A cross-sectional study of polycyclic aro-
matic hydrocarbon-DNA adducts and polymorphism of glu-
tathione S-transferases among heavy smokers by race/eth-
nicity. Biomarkers. 2003;8:142–155.
26. Ren Q, Murphy SE, Zheng Z, Lazarus P. O-Glucuronidation
of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-
1-butanol (NNAL) by human UDP-glucuronosyltransferases
2B7 and 1A9. Drug Metab Dispos. 2000;28:1352–60.
27. Bendaly J, Fang JL, Wiener D, Lazarus P. Functional char-
acterization of the UGT1A183Glyand UGT2B7268Tyrpolymor-
phic variants. Scientific Program. 95thAnnual Meeting of the
American Association for Cancer Research. Orlando, Fl.
March 27–31, 2004, p 218.
28. Anderson GD. Sex differences in drug metabolism: cyto-
chrome P-450 and uridine diphosphate glucuronosyltrans-
ferase. J Gend Specif Med. 2002;5:25–33.
29. Kassie F, Uhl M, Rabot S, Grasl-Kraupp B, Verkerk R, Kundi
M, Chabicovsky M, et al. Chemoprevention of 2-amino-3-
methylimidazo[4,5-f]quinoline (IQ)-induced colonic and
hepatic preneoplastic lesions in the F344 rat by cruciferous
vegetables administered simultaneously with the carcino-
gen. Carcinogenesis. 2003;24:255–261.
30. van der Logt EM, Roelofs HM, Nagengast FM, Peters WH.
Induction of rat hepatic and intestinal UDP-glucuronosyl-
transferases by naturally occurring dietary anticarcinogens.
Carcinogenesis. 2003;24:1651–1656. E-pub 2003 Jul 17.
31. Le Bon AM, Vernevaut MF, Guenot L, Kahane R, Auger J,
Arnault I, et al. Effects of garlic powders with varying alliin
contents on hepatic drug metabolizing enzymes in rats. J
Agric Food Chem. 2003;51:7617–23.
32. Hecht SS, Carmella SG, Kenney PM, Low SH, Arakawa K, Yu
MC. Effects of cruciferous vegetable consumption on uri-
nary metabolites of the tobacco-specific lung carcinogen
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in Singa-
pore Chinese. Cancer Epidemiol Biomarkers Prev. 2004;13:
33. Hecht SS. Human urinary carcinogen metabolites: biomar-
kers for investigating tobacco and cancer. Carcinogenesis.
34. Maser E, Richter E, Friebertshauser J. The identification of
11 beta-hydroxysteroid dehydrogenase as carbonyl reduc-
tase of the tobacco-specific nitrosamine 4-(methylnitro-
samino)-1-(3-pyridyl)-1-butanone. Eur J Biochem. 1996;238:
35. Maser E. Stress, hormonal changes, alcohol, food constitu-
ents and drugs: factors that advance the incidence of to-
bacco smoke-related cancer? TIPS. 1997;18:270–275.
36. Anderson KE, Carmella SG, Ye M, Bliss RL, Le C, Murphy L,
Hecht SS. Metabolites of a tobacco-specific lung carcinogen
in nonsmoking women exposed to environmental tobacco
smoke. J Natl Cancer Inst. 2001;93:378–381.
37. Gadgeel SM, Kalemkerian GP. Racial differences in lung
cancer. Cancer Metastasis Rev. 2003;22:39–46.
38. Krieger N. Refiguring “race”: epidemiology, racialized biol-
ogy, and biological expressions of race relations. Int J Health
39. Feigelman W, Gorman B. Toward explaining the higher in-
cidence of cigarette smoking among black Americans. J Psy-
choactive Drugs. 1989;21:299–305.
40. Colby JP Jr, Linsky AS, Straus MA. Social stress and state-to-
state differences in smoking and smoking related mortality
in the United States. Soc Sci Med. 1994;38:373–381.
41. Romano PS, Bloom J, Syme SL. Smoking, social support, and
hassles in an urban African-American community. Am J
Public Health. 1991;81:1415–1422.
42. Chang SI, Djordevic MV, Zhang J, Hosey J, Chen S, Tika M,
et al. Cigarette smoking topography, delivered doses of
smoke toxins, and excreted metabolites of smoke constitu-
ents: a comparison of African-American and white Ameri-
can smokers. Scientific Program. 95thAnnual Meeting of the
American Association for Cancer Research. Orlando, Fl.
March 27–31,2004, p 168.
1426CANCER April 1, 2005 / Volume 103 / Number 7