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Carcinogenesis |
University of Minnesota Cancer Center [S. S. H., S. G. C., M. C., J. F. D. K., A. T. M., S. E. M.], College of Pharmacy [C. L. Z.], and Department of Psychiatry, University of Minnesota [J. A. J., D. K. H.], Minneapolis, Minnesota 55455
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(1)
. In rodents and humans, NNK is rapidly metabolized to its carbonyl reduction product NNAL, which is also a pulmonary carcinogen in rats and mice. NNAL is O-glucuronidated to give NNAL-Gluc, which is excreted in urine. Urinary NNAL and NNAL-Gluc are excellent biomarkers for NNK uptake in smokers and in people exposed to environmental tobacco smoke (1)
. NNK itself is not detected in urine due to its extensive metabolism. Both NNAL and NNK undergo metabolic hydroxylation at the carbons adjacent to the nitrosamino nitrogen. These cytochrome P450-catalyzed 
-hydroxylation reactions generate intermediates that react with DNA, causing permanent mutations associated with tumor induction (1)
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Smokers were recruited through newspaper advertisements and local press releases. Subjects were initially screened over the telephone. They must have smoked at least 15 cigarettes per day for the past year. Potential subjects were scheduled for a screening visit at the University of Minnesota Tobacco Research Programs clinic. At the screening visit, they filled out a questionnaire regarding their smoking history and completed a medical history form. Smoking status was confirmed by salivary cotinine and expired CO. Subjects were excluded if they had any current medical condition, used prescribed medications, or had a psychiatric diagnosis. Qualified subjects smoked normally for 7 days prior to their quit date. Two 24-h urine samples were collected on 2 consecutive days during this period and analyzed for nicotine, cotinine, NNAL, and NNAL-Gluc. Blood samples were also obtained. Subjects reported to the study clinic on the evening before their quit date. Data were collected on vital signs, concomitant medications, CO levels, and self-reported smoking status. They were randomly assigned to active nicotine patch (15-mg Nicotrol Nicotine Transdermal System), or no patch. Adjunct counseling consisted of group counseling by trained smoking cessation group counselors over the course of 7 weeks, with patch use for 6 of those weeks. Subjects attended biweekly sessions for 3 weeks and weekly sessions for 4 weeks. Follow up visits occurred at 4, 8, 12, and 26 weeks post-treatment. Beginning at the quit date, subjects visited the study center and provided 24 h urine at days 7, 21, 42, 70, 98, and 126 thereafter. Some subjects also provided samples 196, 211, and 281 days after quitting. The urine was analyzed for nicotine, cotinine, NNAL, NNAL-Gluc, and creatinine. At each visit, data were collected on expired CO, vital signs, concomitant medications, and self-reported smoking status.
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Nicotine and cotinine were analyzed by a method similar to those described previously (11 , 12) . [CD3]Cotinine and [CD3]nicotine (Sigma Chemical Co., St. Louis, MO; 500 ng of each for active smokers; 500 ng cotinine and 50 ng nicotine in quitters) were used as internal standards. They were added to urine (0.2 ml from active smokers and 1 ml from quitters). The volume of urine from the active smokers was adjusted to 1 ml. It was mixed with 1 ml of 50% aqueous K2CO3 and then extracted once with 2 ml of CH2Cl2. The CH2Cl2 layer was separated and mixed with 200 µl of CH3OH. This solution was concentrated under a gentle stream of N2 to a total volume of 100–200 µl of CH3OH and then analyzed by gas chromatography-mass spectrometry-selected ion monitoring (model 6890 gas chromatograph equipped with an autosampler and model 5973 Mass Selective Detector; Hewlett Packard, Palo Alto, CA). The GC was equipped with a Merlin septum and an HP-5 fused silica capillary column (30 m, 0.25 mm inner diameter, 0.25-µm film thickness). The injection port temperature was 250°C, and the injection mode was splitless. Deactivated injection port liners were used as described (11) . The oven temperature was 70°C for 0.5 min and then increased to 180°C at 10°C/min, held for 1 min, increased to 275°C at 50°C/min, held for 5 min, and returned to initial conditions. The carrier gas was He at a flow rate of 1 ml/min. The mass spectrometry transfer line was heated at 300°C. From 0 to 10 min, we monitored m/z 84 [C4H7NCH3]+, 87[C4H7NCD3]+, 162 [M+, nicotine], and 165[M+, [CD3]nicotine]; after 10 min, we monitored m/z 98 [C4H5ONCH3]+, 101 [C4H5ONCD3]+, 176 [M+, cotinine], and 179 [M+, [CD3]cotinine]. The retention time of nicotine was 8.37 min, and that of cotinine was 12.78 min. The internal standards eluted 0.02 min before the analytes. Because the samples were stored in base, nicotine-N-glucuronide, and cotinine-N-glucuronide were hydrolyzed to free nicotine and cotinine by heating at 80°C for 1 h. The nicotine values include nicotine and nicotine-N-glucuronide, and the cotinine values include cotinine and cotinine-N-glucuronide.
Blood Collection and Analysis.
Blood was collected in EDTA-containing vacutainers. RBCs and plasma were separated, the RBCs were washed three times with two volumes of 0.9% saline, and both fractions were stored at -80°C until analysis. The washed RBC pellet from 14 ml of blood was lysed with H2O with vortexed. The mixture was extracted twice with hexane. The hexane extracts were discarded. The aqueous phase was extracted three times with CH2Cl2, and the combined extracts were analyzed for unconjugated NNAL and NNK as described for urine. The aqueous phase was treated with 0.1 N NaOH, with sonication for 1 h at room temperature. After neutralization, it was extracted three times with equal volumes of CH2Cl2 and then analyzed for NNAL and NNK as above. The aqueous phase was acidified to a concentration of 0.1 N HCl. It was sonicated for 1 h at room temperature, neutralized, and extracted three times with CH2Cl2, and the extracts analyzed for NNAL and NNK. Plasma from the same blood sample was treated and analyzed the same way as RBCs.
Other Analyses.
CO was determined with a Medical Gas Monitor, Bedfont Scientific, Ltd. (Kent, United Kingdom). Creatinine was assayed by Fairview-University Medical Center Diagnostic Laboratories (Minneapolis, MN) using Vitros CREA slides.
Pharmacokinetic Analyses.
The urinary excretion rates (dXe/dt, pmol per 24 h) of NNAL and NNAL-Gluc were plotted separately as a function of time (days postquitting) with the rate at time zero being the steady-state urinary excretion rate on the last day of smoking. The rate-time plots appeared to be biphasic and were fit to a bi-exponential model with the use of KaleidaGraph (Version 3.08d; Synergy Software):
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The volume of distribution in the ß-phase (Vß) was also calculated:
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Rat Study.
Six male F-344 rats weighing about 250 g were obtained from Charles River Breeding Laboratories (Kingston, NY). They were maintained on NIH-07 diet. Two groups of three rats each were used for chronic and acute studies. In the chronically treated group, three rats were given NNK in the drinking water at 2 ppm for 14 days. After 2 weeks, they were placed in metabolism cages. NNK was continued in the drinking water, and 24-h urine was collected from the rats. They were then returned to conventional cages for an additional 2 weeks of NNK treatment. NNK administration ceased after a total of 28 days. The rats were then placed in metabolism cages, and their urine was collected for 5 days. In the acutely treated group, three rats were given NNK in the drinking water at 2 ppm for 2 days. They were then transferred to metabolism cages and urine was collected for the next 5 days. Urine from both groups of rats was analyzed for NNAL and NNAL-Gluc as above. For all rats, mean daily NNK dose was estimated to be 0.22 µmol (13)
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Statistical Analysis.
A paired t test was used to compare and ß from NNAL and NNAL-Gluc. ANOVA for repeated measurements was used to compare the elimination of NNAL and NNAL-Gluc in subjects who did or did not use the nicotine patch.
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RESULTS |
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Baseline data are summarized in Table 1
. The mean level ± SD and range of NNAL per 24 h were 944 ± 517 pmol and 180-2080 pmol, respectively. The corresponding values for NNAL-Gluc per 24 h were 2200 ± 1130 pmol and 280-4970 pmol. NNAL plus NNAL-Gluc correlated with cotinine (R = 0.43; P = 0.0079) and nicotine (R = 0.44; P = 0.006). These data are consistent with previous observations (9
, 10)
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. In this analysis, NNAL is released from NNAL-Gluc by hydrolysis with ß-glucuronidase. After extraction and purification, it is silylated to give NNAL-TMS, which is analyzed by GC-TEA. The NNAL-TMS peaks at the later time points were quite small. For representative samples, the identities of these peaks as NNAL-TMS were confirmed by gas chromatography-tandem mass spectrometry.
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depicts the mean excretion rate data for NNAL and NNAL-Gluc in the 27 subjects. Of the 27 individuals, 22 showed clear biexponential pharmacokinetics for NNAL, and 23 showed biexponential pharmacokinetics for NNAL-Gluc. One subject could not be fit to any pharmacokinetic model due to variability in his data, and the excretion rate data in the others appeared to be monoexponential. In general, there was a relatively rapid initial decline in excretion rates followed by a slower terminal phase. Although the NNAL-Gluc excretion rate was significantly higher in all urine samples, the excretion rate-time profiles for NNAL and NNAL-Gluc were parallel, indicating that NNAL-Gluc was formation rate limited in its elimination. Indeed, there was no significant difference in either the distribution rate constant () or elimination rate constants (ß) for the two compounds (Table 2)
. The distribution half-life for the two compounds was 3–4 days, and the elimination half-life was 40–45 days, indicating prolonged retention of NNAL and NNAL-Gluc after cessation of smoking.
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Individual values of NNAL plus NNAL-Gluc per 24 h during the cessation period were compared to the mean baseline values for each subject. The baseline values were set as 100%, and the percentage of baseline for each of the 14 people who did not use the nicotine patch was calculated at each time point after cessation. Similar data were obtained for the 13 people who used the nicotine patch. Because there was no significant difference (P = 0.93) between the data for the patch and nonpatch subjects, they were combined. The mean decay of NNAL plus NNAL-Gluc per 24 h, expressed as a percentage of the baseline value, is illustrated for all 27 subjects in Fig. 5A
. A similar analysis for NNAL-Gluc is shown in Fig. 5B
and for NNAL in Fig. 5C
. Similar results were obtained when NNAL and NNAL-Gluc were expressed per ml of urine or per mg of creatinine.
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. The 21–98-day cotinine data and the 7–98-day nicotine data are not significantly different from background levels.
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The renal clearance of NNAL in the three smokers for whom blood and urine data were available was 9.8 ± 8.0 ml/min. Assuming that NNAL was not bound to plasma proteins, as indicated by the hydrolysis experiments, it appears that NNAL is substantially reabsorbed in the renal tubules. The total body clearance of NNAL in these subjects was 61.4 ± 35.4 ml/min, suggesting that NNAL is a relatively low-clearance compound. With the use of the average value of ß found in the subjects who had quit smoking, the volume of distribution in the ß-phase for these three subjects was calculated to be 3800 ± 2100 liters, indicating substantial distribution into the tissues.
The persistence of NNAL and NNAL-Gluc was also investigated in rats. Rats were treated with 2 ppm NNK in the drinking water for 28 days (chronic administration) or 2 days (acute). In the rats treated chronically, levels of NNAL and NNAL-Gluc in urine were 332 ± 30.1 pmol/ml and 371 ± 49.8 pmol/ml, respectively, at day 15, which represents 5–10% of the NNK dose, in agreement with a previous study (14)
. Data on the persistence of these metabolites after cessation of treatment are summarized in Table 3
. In the chronically treated rats, levels of NNAL decreased rapidly, reaching <1% of the baseline value by day 2 of cessation. However, NNAL-Gluc levels in urine declined much more slowly and were still 5.9% of baseline 5 days after cessation of treatment. The ß-phase of NNAL-Gluc appeared to be prolonged in the chronically treated rats, leading to a significantly longer terminal half-life than in the acute treatment (8.06 versus 2.12 days).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and 6
). After 3 weeks, NNAL plus NNAL-Gluc levels in urine were still 15.3% of baseline, whereas the amounts of nicotine and cotinine were indistinguishable from background levels. The value of t1/2ß for cotinine has been estimated as 16.5 h upon smoking cessation (8)
whereas the corresponding values for NNAL and NNAL-Gluc are 45.2 and 39.6 days, respectively. The slow decay of NNAL and NNAL-Gluc after smoking cessation is due to their slow clearance from the body as well as the presence of a high-affinity compartment where NNK, NNAL, and/or NNAL-Gluc is/are retained or sequestered and released slowly.
The excretion rate-time profiles for NNAL and NNAL-Gluc were parallel and the fitted rate constants and ß were not significantly different for the two compounds. The elimination of NNAL-Gluc is likely to be rate controlled by its formation from NNAL. Therefore, the pharmacokinetics of NNAL effectively controls the excretion rate profile of NNAL-Gluc.
NNAL itself has a very low clearance and a large volume of distribution, the consequence of which is a terminal half-life of 
45 days. The renal clearance of NNAL is significantly lower than the glomerular filtration rate, indicating substantial reabsorption from the renal tubules. The total body clearance of NNAL is also quite low, and a comparison to hepatic liver blood flow indicates that NNAL would be considered a low-extraction ratio drug.
One of the difficulties with the pharmacokinetic analysis is knowing precisely the dose of NNAL to which the subject is exposed. The daily dose was estimated from the number of cigarettes smoked and the amount of NNK contained in cigarettes. It is well known that smoking conditions can affect NNK yield (15 , 16) . The conversion of NNK to NNAL is also an estimate. If the actual dose of NNAL were lower than we estimated, the clearance of NNAL would be proportionally smaller. This does not invalidate the finding of a low total body clearance for NNAL.
Although the inefficient clearance mechanisms contribute to the long half-life of NNAL, its substantial volume of distribution is probably more important. A large volume of distribution is not without precedent and other basic compounds, including choloroquine (116–285 liters/kg), amiodarone (65 liters/kg), and desipramine (24–60 liters/kg) have large volumes of distribution in humans (17 , 18) .
NNK, NNAL, nicotine, and cotinine share some structural features. They are all 3-substituted pyridines and they all have a four-carbon chain or ring and a methyl-substituted nitrogen. All are relatively water-soluble compounds. Nicotine is a stronger base than the other three. Clearly, the pyridine ring itself is not responsible for the retention or sequestration because all four compounds have this structural feature. The carbonyl group of NNK is one structural feature that could lead to retention in the body. NNK could potentially form Schiff bases with amino groups of proteins, although there are no reports of this type of binding. We could find no evidence for reversible binding of NNK to blood proteins of smokers.
Several whole-body autoradiographic studies have been carried out after single doses of radiolabeled NNK to rats, hamsters, mice, or marmoset (19, 20, 21, 22, 23) . In the rat, the highest labeling 4 days after injection of NNK is found in the nasal mucosa, bronchi, and trachea. Most of this radioactivity is irreversibly bound to tissue macromolecules, probably in the form of adducts that would not regenerate NNK or NNAL (1 , 19) . Four h and 24 h after treatment of Syrian golden hamsters with NNK, radioactivity was observed in the nasal mucosa, trachea, bronchial tree, liver, and eye melanin (21) . Similar results were obtained in mice (20) . In the marmoset monkey, radioactivity was concentrated in the liver, nasal mucosa, eye melanin, and ceruminous ear glands 4 h after injection of NNK (22) . Binding to melanin may be a reflection of the basicity of NNK and is also observed in animals treated with nicotine, cotinine, and other basic compounds (23, 24, 25) . Collectively, the presently available whole-body autoradiographic data provide little insight on the nature of the site in which NNK or NNAL is sequestered in humans. However, a recent study of NNK disposition after instillation in the canine trachea demonstrated the presence of a slow clearance phase from the trachea (26) . NNK was distributed within the entire depth of the mucosa to the tracheal cartilage; a portion was conspicuously bound to the mucin component of the mucous lining layer. The slow clearance phase in this study was attributed to reversible binding to mucin (26) .
The data from the acute and chronic studies in rats showed similar biphasic pharmacokinetics. However, the levels of NNAL appeared to reach background before the terminal phase was apparent. It is interesting to note that the terminal phase of NNAL-Gluc was longer in the chronic study than in the acute study. This would be consistent with a compound having a large volume of distribution. After acute dosing, relative to the blood compartment, there is not as much drug residing in the tissue compartments. Therefore, upon the cessation of the acute dosing, the elimination appears to be more rapid and less dependent upon redistribution from the tissue space. In contrast, when the tissue compartments contain more drug, as after chronic dosing, the elimination from the body will be much more dependent upon redistribution from the tissue space.
There was no evidence for endogenous formation of NNK in this study. If endogenous formation of NNK were occurring, we would have expected higher levels of NNK metabolites in nicotine patch users compared to those who did not use the patch. This was not observed. This is consistent with a previous study in rats in which we did not detect any evidence for endogenous formation of NNK after treatment of rats with nicotine and sodium nitrite (27) . However, endogenous formation of N'-nitrosonornicotine and N'-nitrosoanabasine was observed in that study.
Although the retention of NNAL and NNAL-Gluc was longer than expected, the results clearly demonstrate that smoking cessation diminishes exposure to the pulmonary carcinogen NNK and that, ultimately, this substance and its metabolites are eliminated from the body. Furthermore, use of the nicotine patch does not affect the rate of elimination of NNAL and NNAL-Gluc. The decrease in carcinogen exposure upon smoking cessation will result in a decrease in risk. Because NNAL and NNAL-Gluc can be readily quantified in human urine, it is possible that measurements of these NNK metabolites could be used as a positive reinforcement device to encourage and maintain smoking cessation.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This study was supported by National Cancer Institute Grant CA-44377. 
2 To whom requests for reprints should be addressed, at University of Minnesota Cancer Center, Box 806 Mayo, 420 Delaware Street SE, Minneapolis, MN 55455.
3 The abbreviations used are: NNAL, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; NNAL-Gluc, 4-[(methylnitrosamino)-1-(3-pyridyl)but-1-yl]-ß-O-D-glucosiduronic acid; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; GC-TEA, gas chromatography-nitrosamine-selective detection; TMS, trimethylsilyl ether.
Received 8/19/98. Accepted 12/ 2/98.
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nbaek K., Tnnesen P., Poulsen H. E. Effect of smoking cessation on oxidative DNA modification estimated by 8-oxo-7,8-dihydro-2'-deoxyguanosine excretion. Carcinogenesis (Lond.), 19: 347-351, 1998.This article has been cited by other articles:
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  I. Stepanov, P. Upadhyaya, S. G. Carmella, R. Feuer, J. Jensen, D. K. Hatsukami, and S. S. Hecht Extensive Metabolic Activation of the Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Smokers Cancer Epidemiol. Biomarkers Prev., July 1, 2008; 17(7): 1764 - 1773. [Abstract] [Full Text] [PDF]
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I. Stepanov and S. S. Hecht Detection and Quantitation of N'-Nitrosonornicotine in Human Toenails by Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry Cancer Epidemiol. Biomarkers Prev., April 1, 2008; 17(4): 945 - 948. [Abstract] [Full Text] [PDF]
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 S S Hecht, S G Carmella, A Edmonds, S E Murphy, I Stepanov, X Luo, and D K Hatsukami Exposure to nicotine and a tobacco-specific carcinogen increase with duration of use of smokeless tobacco Tob. Control, April 1, 2008; 17(2): 128 - 131. [Abstract] [Full Text] [PDF]
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J. H. Lubin, N. Caporaso, D. K. Hatsukami, A. M. Joseph, and S. S. Hecht The Association of a Tobacco-Specific Biomarker and Cigarette Consumption and Its Dependence on Host Characteristics Cancer Epidemiol. Biomarkers Prev., September 1, 2007; 16(9): 1852 - 1857. [Abstract] [Full Text] [PDF]
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L. G. Spector, S. S. Hecht, S. Ognjanovic, S. G. Carmella, and J. A. Ross Detection of Cotinine in Newborn Dried Blood Spots Cancer Epidemiol. Biomarkers Prev., September 1, 2007; 16(9): 1902 - 1905. [Abstract] [Full Text] [PDF]
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S. S. Hecht, S. G. Carmella, S. E. Murphy, W. T. Riley, C. Le, X. Luo, M. Mooney, and D. K. Hatsukami Similar Exposure to a Tobacco-Specific Carcinogen in Smokeless Tobacco Users and Cigarette Smokers Cancer Epidemiol. Biomarkers Prev., August 1, 2007; 16(8): 1567 - 1572. [Abstract] [Full Text] [PDF]
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 M. J. Stark, K. Rohde, J. E. Maher, B. A. Pizacani, C. W. Dent, R. Bard, S. G. Carmella, A. R. Benoit, N. M. Thomson, and S. S. Hecht The Impact of Clean Indoor Air Exemptions and Preemption Policies on the Prevalence of a Tobacco-Specific Lung Carcinogen Among Nonsmoking Bar and Restaurant Workers Am J Public Health, August 1, 2007; 97(8): 1457 - 1463. [Abstract] [Full Text] [PDF]
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I. Stepanov, S. S. Hecht, B. Lindgren, P. Jacob III, M. Wilson, and N. L. Benowitz Relationship of Human Toenail Nicotine, Cotinine, and 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol to Levels of These Biomarkers in Plasma and Urine Cancer Epidemiol. Biomarkers Prev., July 1, 2007; 16(7): 1382 - 1386. [Abstract] [Full Text] [PDF]
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C. J. Gallagher, J. E. Muscat, A. N. Hicks, Y. Zheng, A.-M. Dyer, G. A. Chase, J. Richie, and P. Lazarus The UDP-Glucuronosyltransferase 2B17 Gene Deletion Polymorphism: Sex-Specific Association with Urinary 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol Glucuronidation Phenotype and Risk for Lung Cancer Cancer Epidemiol. Biomarkers Prev., April 1, 2007; 16(4): 823 - 828. [Abstract] [Full Text] [PDF]
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S. S. Hecht, S. G. Carmella, K.-A. Le, S. E. Murphy, A. J. Boettcher, C. Le, J. Koopmeiners, L. An, and D. J. Hennrikus 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides in the urine of infants exposed to environmental tobacco smoke. Cancer Epidemiol. Biomarkers Prev., May 1, 2006; 15(5): 988 - 992. [Abstract] [Full Text] [PDF]
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I. Stepanov, S. S. Hecht, G. Duca, and I. Mardari Uptake of the Tobacco-Specific Lung Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-Butanone by Moldovan Children Cancer Epidemiol. Biomarkers Prev., January 1, 2006; 15(1): 7 - 11. [Abstract] [Full Text] [PDF]
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A. M. Joseph, S. S. Hecht, S. E. Murphy, S. G. Carmella, C. T. Le, Y. Zhang, S. Han, and D. K. Hatsukami Relationships between Cigarette Consumption and Biomarkers of Tobacco Toxin Exposure Cancer Epidemiol. Biomarkers Prev., December 1, 2005; 14(12): 2963 - 2968. [Abstract] [Full Text] [PDF]
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S. G. Carmella, S. Han, P. W. Villalta, and S. S. Hecht Analysis of Total 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol in Smokers' Blood Cancer Epidemiol. Biomarkers Prev., November 1, 2005; 14(11): 2669 - 2672. [Abstract] [Full Text] [PDF]
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 D. K. Hatsukami, M. Kotlyar, S. Allen, J. Jensen, S. Li, C. Le, and S. Murphy Effects of Cigarette Reduction on Cardiovascular Risk Factors and Subjective Measures Chest, October 1, 2005; 128(4): 2528 - 2537. [Abstract] [Full Text] [PDF]
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O. E. Tulunay, S. S. Hecht, S. G. Carmella, Y. Zhang, C. Lemmonds, S. Murphy, and D. K. Hatsukami Urinary Metabolites of a Tobacco-Specific Lung Carcinogen in Nonsmoking Hospitality Workers Cancer Epidemiol. Biomarkers Prev., May 1, 2005; 14(5): 1283 - 1286. [Abstract] [Full Text] [PDF]
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I. Stepanov and S. S. Hecht Tobacco-Specific Nitrosamines and Their Pyridine-N-glucuronides in the Urine of Smokers and Smokeless Tobacco Users Cancer Epidemiol. Biomarkers Prev., April 1, 2005; 14(4): 885 - 891. [Abstract] [Full Text] [PDF]
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) and NNAL-Gluc (
) in 27 subjects as a function of time after smoking cessation. Note that excretion rates are presented on a semilogarithmic scale, which exaggerates the appearance of the error bars at the lower range of the Y axis. Data points, means; bars, SD.
