Biomedical subjects

Steven G Carmella

Publications and source records attributed to Steven G Carmella.

At least 19 recordsLinked to original sources

PubMed2006

Partial purification from hot dogs of N-nitroso compound precursors and their mutagenicity after nitrosation.

Hot dogs contain apparent N-nitroso compounds (ANC) and ANC precursors (ANCP). ANCP purification was followed by nitrosation, sulfamic acid treatment, and analysis for ANC. Aqueous hot dog extracts were adsorbed on silica gel, which was eluted with MeCN and MeOH. The MeOH eluate was adsorbed on cation exchange resin (H+ form) and eluted with NH4OH. Eluted ANCP traveled at moderate speeds in high-performance liquid chromatography (HPLC) on amino and Pb2+ columns. Gas chromatography-mass spectrometry (GC-MS) of trimethylsilyl (TMS) derivatives of crude water extract indicated the presence of glycerol, phosphate, lactic acid, and two monosaccharides. GC-MS of TMS derivatives of Pb2+ column HPLC eluates indicated that ANCP included 1-deoxy-N-1-glucosyl glycine. The nitrosated NH4OH eluate showed 4x background mutagenic activity for Salmonella typhimurium TA-100. Un-nitrosated fractions showed 2x background activity. Although tryptophan nitrosation gave 88% ANC yield, tryptophan is probably not a major ANCP in hot dogs. Hot dog patties prepared with or without sucrose or glucose showed similar ANC and ANCP levels. We discuss possible implications of these findings for the etiology of colon cancer.

Amino Acids↗

PubMed2006

Perturbation of glucose flux in the liver by decreasing F26P2 levels causes hepatic insulin resistance and hyperglycemia.

Hepatic insulin resistance is one of the characteristics of type 2 diabetes and contributes to the development of hyperglycemia. How changes in hepatic glucose flux lead to insulin resistance is not clearly defined. We determined the effects of decreasing the levels of hepatic fructose 2,6-bisphosphate (F26P(2)), a key regulator of glucose metabolism, on hepatic glucose flux in the normal 129J mice. Upon adenoviral overexpression of a kinase activity-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, the enzyme that determines F26P(2) level, hepatic F26P(2) levels were decreased twofold compared with those of control virus-treated mice in basal state. In addition, under hyperinsulinemic conditions, hepatic F26P(2) levels were much lower than those of the control. The decrease in F26P(2) leads to the elevation of basal and insulin-suppressed hepatic glucose production. Also, the efficiency of insulin to suppress hepatic glucose production was decreased (63.3 vs. 95.5% suppression of the control). At the molecular level, a decrease in insulin-stimulated Akt phosphorylation was consistent with hepatic insulin resistance. In the low hepatic F26P(2) states, increases in both gluconeogenesis and glycogenolysis in the liver are responsible for elevations of hepatic glucose production and thereby contribute to the development of hyperglycemia. Additionally, the increased hepatic gluconeogenesis was associated with the elevated mRNA levels of peroxisome proliferator-activated receptor-gamma coactivator-1alpha and phosphoenolpyruvate carboxykinase. This study provides the first in vivo demonstration showing that decreasing hepatic F26P(2) levels leads to increased gluconeogenesis in the liver. Taken together, the present study demonstrates that perturbation of glucose flux in the liver plays a predominant role in the development of a diabetic phenotype, as characterized by hepatic insulin resistance.

Adenoviridae↗

PubMed2006

Identification of cyanidin glycosides as constituents of freeze-dried black raspberries which inhibit anti-benzo[a]pyrene-7,8-diol-9,10-epoxide induced NFkappaB and AP-1 activity.

Dietary freeze-dried black raspberries inhibit tumor induction by N-nitrosomethylbenzylamine in the rat esophagus, but the constituents responsible for this chemopreventive activity have not been identified. We fractionated freeze-dried black raspberries and used mouse epidermal JB6 Cl 41 cells stably transfected with either a nuclear factor kappa B (NFkappaB)- or an activator protein 1 (AP-1)-luciferase reporter, and treated with racemic anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), to assess the inhibitory effects of the fractions. The ethanol and water extracts of the freeze-dried black raspberries had inhibitory activity and these extracts were fractionated by HPLC to give several bioactive fractions. Further HPLC analysis yielded multiple subfractions, some of which inhibited BPDE-induced NFkappaB activity. Major constituents of the most active subfractions were identified by their spectral properties and in comparison with standards as cyanidin-3-O-glucoside, cyanidin 3-O-(2(G)-xylosylrutinoside) and cyanidin 3-O-rutinoside. Analysis of freeze-dried black raspberries indicated that these three components comprised approximately 3.4% of the material by dry weight. Consistent with these results, standard cyanidin-3-O-glucoside and cyanidin chloride were also good inhibitors of BPDE-induced NFkappaB activity. The results of this study demonstrate that cyanidin glycosides of freeze-dried black raspberries are bioactive compounds which could account for at least some of the chemopreventive activity observed in animal models.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMed2006

Oral creatine supplementation in humans does not elevate urinary excretion of the carcinogen N-nitrososarcosine.

OBJECTIVE: Creatine is a popular oral supplement in athletes and may have therapeutical potential in neuromuscular diseases. It has been hypothesized that creatine ingestion can lead to increased formation of the carcinogen N-nitrososarcosine. METHODS: We investigated in a double-blind, placebo-controlled study the urinary excretion of N-nitrososarcosine after 1-wk high-dose (20 g/d) and 20-wk low-dose (5 g/d) creatine supplementation in healthy humans. RESULTS AND CONCLUSION: Creatine ingestion does not systematically increase urinary N-nitrososarcosine excretion.

Administration, Oral↗

PubMed2006

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides in the urine of infants exposed to environmental tobacco smoke.

Biomarkers of carcinogen uptake could provide important information pertinent to the question of exposure to environmental tobacco smoke (ETS) in childhood and cancer development later in life. Previous studies have focused on exposures before birth and during childhood, but carcinogen uptake from ETS in infants has not been reported. Exposures in infants could be higher than in children or adults because of their proximity to parents who smoke. Therefore, we quantified 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL) in the urine of 144 infants, ages 3 to 12 months, who lived in homes with parents who smoked. Total NNAL is an accepted biomarker of uptake of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Cotinine and its glucuronide (total cotinine) and nicotine and its glucuronide (total nicotine) were also quantified. Total NNAL was detectable in 67 of 144 infants (46.5%). Mean levels of total NNAL in the 144 infants were 0.083 +/- 0.200 pmol/mL, whereas those of total cotinine and total nicotine were 0.133 +/- 0.190 and 0.069 +/- 0.102 nmol/mL, respectively. The number of cigarettes smoked per week in the home or car by any family member when the infant was present was significantly higher (P < 0.0001) when NNAL was detected than when it was not (76.0 +/- 88.1 versus 27.1 +/- 38.2). The mean level of NNAL detected in the urine of these infants was higher than in most other field studies of ETS exposure. The results of this study show substantial uptake of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in infants exposed to ETS and support the concept that persistent ETS exposure in childhood could be related to cancer later in life.

Biomarkers↗

PubMed2006

Comparison of polymorphisms in genes involved in polycyclic aromatic hydrocarbon metabolism with urinary phenanthrene metabolite ratios in smokers.

The hypothesis that interindividual differences among smokers in the metabolism of polycyclic aromatic hydrocarbons (PAH) are related to lung cancer risk has been extensively investigated in the literature. These studies have compared lung cancer risk in groups of smokers with or without polymorphisms in genes involved in PAH metabolism. We believe that carcinogen metabolite phenotyping, involving the actual measurement of PAH metabolites, would be a better way to investigate differences in lung cancer risk. With this goal in mind, we have developed methods for quantifying phenanthrene metabolites in urine. Phenanthrene is the simplest PAH with a bay region, a feature closely associated with carcinogenicity. The urinary metabolite r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT) is a measure of metabolic activation, whereas phenanthrols (HOPhe) are a measure of detoxification. In this study, we quantified urinary PheT/HOPhe ratios in 346 smokers who were also genotyped for 11 polymorphisms in genes involved in PAH metabolism: CYP1A1MspI, CYP1A1I462V, CYP1B1R48G, CYP1B1A119S, CYP1B1L432V, CYP1B1N453S, EPHX1Y113H, EPHX1H139R, GSTP1I105V, GSTP1A114V, and GSTM1 null. The geometric mean molar PheT/3-HOPhe ratio was 4.08 (95% confidence interval, 3.79-4.39). Ten percent of the smokers had PheT/3-HOPhe ratios of > or =9.90. We found a significant association between the presence of the CYP1A1I462V polymorphism and high PheT/3-HOPhe ratios (P = 0.02). This effect was particularly strong in females and in combination with the GSTM1 null polymorphism. In contrast, the CYP1B1R48G and CYP1B1A119S polymorphisms were associated with significantly lower PheT/3-HOPhe ratios, particularly in Blacks. There were no consistent significant effects of any of the other polymorphisms on PheT/3-HOPhe ratios. The highest 10% of PheT/3-HOPhe ratios could not be predicted by the presence of any of the 11 polymorphisms individually or by certain combinations. The effects of the CYP1A1I462 polymorphism observed here, particularly in combination with GSTM1 null, are quite consistent with reports in the literature. However, the results of this study indicate that genotyping is not an effective way to predict PAH metabolism at least as represented by PheT/HOPhe ratios.

Adolescent↗

PubMed2006

Combined analysis of r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in smokers' plasma.

Polycyclic aromatic hydrocarbons (PAH) and tobacco-specific nitrosamines, such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are widely accepted to be two important types of lung carcinogens in cigarette smoke. In this study, we have developed a method to estimate individual uptake of these compounds by quantifying r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in 1 mL of smokers' plasma. PheT and NNAL are biomarkers of PAH and NNK uptake, respectively. [D10]PheT and [pyridine-D4]NNAL were added to plasma as internal standards. The plasma was treated with beta-glucuronidase to release any conjugated PheT and NNAL. The analytes were enriched by solid-phase extraction on a mixed mode cation exchange cartridge and the PheT fraction was further purified by high-performance liquid chromatography. The appropriate fractions were analyzed by gas chromatography-negative ion chemical ionization-mass spectrometry for PheT and liquid chromatography-electrospray ionization-mass spectrometry for NNAL. The method was sensitive (limits of quantitation: PheT, 13 fmol/mL; NNAL, 3 fmol/mL), accurate, and precise. Levels of PheT and NNAL in plasma from 16 smokers averaged 95 +/- 71 and 36 +/- 21 fmol/mL, respectively, which are approximately 1% to 2% of the amounts found in urine. This method should be useful in molecular epidemiology studies of carcinogen uptake and lung cancer in smokers.

Biomarkers↗

PubMed2006

Toxicant exposure in cigarette reducers versus light smokers.

BACKGROUND: The extent of exposure to tobacco toxicants in smokers who have reduced their cigarette intake compared with smokers who are light smokers is relatively unknown. The goal of this study is to investigate the occurrence of compensatory smoking in reducers compared with light smokers by measuring toxicant exposure. METHODS: Participants in two smoking reduction intervention studies (N = 64) were selected for comparison with a group of light smokers (N = 62) who smoked the same number of cigarettes as the reducers. A compensatory smoking score was defined (biomarker level for reducer/biomarker level for light smoker) and calculated for urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (total NNAL), metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone, to measure the degree of smoking compensation in reducers when compared with the light smokers. RESULTS: The mean level of creatinine-adjusted total NNAL for reducers was over twice that of light smokers even when they smoked about the same number of cigarettes per day. The difference of the mean total NNAL concentrations between light smokers and reducers was highly significant (P < 0.0001). Wide variability in total NNAL concentrations was also observed in reducers, with the extent of this variability between light smokers and reducers being significantly different (P = 0.0005). The level of individual reduction was shown to be a consistent predictor of compensatory smoking (r = 0.50; adjusted Ps = 0.002), with greater cigarette reduction associated with more compensation. CONCLUSIONS: Compensatory smoking limits the harm reduction value of decreased smoking of cigarettes.

Administration, Cutaneous↗

PubMed2005

Smokeless tobacco topography and toxin exposure.

This study examined the relationship between oral smokeless tobacco (ST) topographical measures and biomarkers of tobacco and carcinogen exposure. During 2 weeks of baseline ad libitum ST use, 54 male participants (mean age=32.1+/-7.5 years) were required to record the time each dip was placed in and removed from their mouths. Urine samples were collected twice during baseline and analyzed for nicotine, cotinine, and their glucuronides (total nicotine and total cotinine) and for metabolites of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL). The results suggest that frequency and duration measures of ST use (p<.01 to p<.001), particularly total dip duration, are significantly correlated with total cotinine, total nicotine, and total NNAL. These results suggest that how long a ST user has tobacco in his mouth is most predictive of tobacco toxin exposure.

Adult↗

PubMed2005

A urinary metabolite of phenanthrene as a biomarker of polycyclic aromatic hydrocarbon metabolic activation in workers exposed to residual oil fly ash.

Residual oil fly ash is a chemically complex combustion product containing a significant component of potentially carcinogenic transition metals and polycyclic aromatic hydrocarbons (PAH). Various biomarkers of PAH exposure have been investigated previously, most notably 1-hydroxypyrene (1-OHP), in urine. In this study, we assessed the utility of r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (trans, anti-PheT), a metabolite of phenanthrene, to detect occupational PAH exposure. Urine samples collected across the workweek were analyzed for 1-OHP and trans, anti-PheT in boilermakers (n = 20) exposed to residual oil fly ash. Median baseline urinary trans, anti-PheT concentrations were 0.50 microg/g creatinine in current tobacco smokers and 0.39 microg/g creatinine in nonsmokers. Median baseline urinary 1-OHP concentrations in smokers and nonsmokers were 0.31 and 0.13 microg/g creatinine, respectively. To study further the effect of smoking exposure on the urinary PAH markers, urinary cotinine was used. Although urinary trans, anti-PheT and 1-OHP concentrations were correlated (Spearman r = 0.63; P < 0.001) for all subjects, the regression coefficient between log-transformed trans, anti-PheT and log 1-OHP was statistically significant only for subjects with low levels of urinary cotinine or for nonsmokers. Each 1-unit increase in log 1-OHP was associated with a 0.77-unit increase (95% confidence interval, 0.45-1.09) in log trans, anti-PheT in subjects with low levels of urinary cotinine (P < 0.001). In these subjects, dichotomized occupational exposure status was a significant predictor of log trans, anti-PheT (P = 0.02) but not of log 1-OHP (P = 0.2). In conclusion, we found that urinary trans, anti-PheT was detected in levels comparable with 1-OHP in occupationally exposed workers, particularly nonsmokers. This study shows that urinary trans, anti-PheT may be an effective biomarker of uptake and metabolic activation of PAHs.

Adult↗

PubMed2005

Similar uptake of lung carcinogens by smokers of regular, light, and ultralight cigarettes.

Cigarette design has changed markedly over the past 60 years and sales-weighed levels of tar and nicotine have decreased. Currently, cigarettes are classified as regular (>14.5 mg tar), light (>6.5-14.5 mg tar), and ultralight (< or =6.5 mg tar), based on a Federal Trade Commission-specified machine-smoking protocol. Epidemiologic studies suggest that there is no difference in lung cancer risk among people who smoke light or ultralight cigarettes compared with regular cigarettes, but the uptake of lung carcinogens in smokers of these types of cigarettes has never been reported. We recruited 175 smokers, who filled out a tobacco use questionnaire in which their current brand was identified as regular, light, or ultralight. Urine samples were collected and analyzed for 1-hydroxypyrene (1-HOP), total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL plus its glucuronides) and total cotinine (cotinine plus its glucuronides). 1-HOP and total NNAL are biomarkers of uptake of polycyclic aromatic hydrocarbons and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, lung carcinogens in cigarette smoke. Total cotinine is a biomarker of nicotine uptake. There were no statistically significant differences in urinary levels of 1-HOP, total NNAL, and total cotinine in smokers of regular, light, and ultralight cigarettes, whether the results were expressed per mg urinary creatinine, per mL of urine, or per mg creatinine divided by cigarettes per day. Levels of machine measured tar were available for the cigarettes smoked by 149 of the subjects. There was no correlation between levels of tar and any of the biomarkers. These results indicate that lung carcinogen and nicotine uptake, as measured by urinary 1-HOP, total NNAL, and total cotinine is the same in smokers of regular, light, and ultralight cigarettes. The results are consistent with epidemiologic studies that show no difference in lung cancer risk in smokers of these cigarettes.

Adult↗

PubMed2005

Urinary metabolites of a tobacco-specific lung carcinogen in nonsmoking hospitality workers.

Exposure of nonsmokers to environmental tobacco smoke results in increased risk for cancer and other diseases. In spite of this finding, some restaurants and bars continue to permit smoking. This study examined the uptake of nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent lung carcinogen, in nonsmokers who work in restaurants and bars that permitted smoking. Urine samples were collected for 24 hours on working and nonworking days and were analysed for total NNAL [the sum of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (NNAL-Glucs)], metabolites of NNK. In addition, urine samples were analysed for total nicotine (nicotine plus nicotine glucuronide), and total cotinine (cotinine plus cotinine-N-glucuronide). The results showed significant increases in urinary levels of total NNAL, total nicotine, and total cotinine on working days compared with nonworking days. The results of this study show that smoke exposure in bars and restaurants may have important health effects on nonsmoking employees, elicited by the increase in carcinogen levels.

Adolescent↗

PubMed2005

Safety and efficacy of weekly oral oltipraz in chronic smokers.

Cigarette smoking is thought to contribute to carcinogenesis by formation of DNA adducts of tobacco smoke constituents leading to genotoxic damage. The dithiolethione, oltipraz, is a putative cancer chemopreventive agent that induces phase II detoxifying enzymes in preclinical models and reduces aflatoxin adducts in humans living in areas with high dietary levels. To determine if oltipraz could reduce adduct levels of tobacco smoke constituents in the lungs and other target organs, chronic smokers were enrolled to one of three arms: 400 or 200 mg/wk oral oltipraz or placebo. Endobronchial tissue and bronchoalveolar lavage were done before and after 12 weeks of drug treatment; peripheral blood, urine, and oral saline rinse were also collected. Toxicity was assessed every 4 weeks. Fifty-nine of the 77 enrolled subjects completed the study. Of those receiving oltipraz, 15% experienced grade 2/3 toxicity, which was predominantly gastrointestinal. All subject withdrawals occurred in the oltipraz groups. There was no significant difference between pre- and post-polycyclic aromatic hydrocarbon-DNA adduct levels in lung epithelial cells measured by immunoperoxidase staining between treatment and placebo groups. Likewise, no significant differences were found in polycyclic aromatic hydrocarbon or benzo(a)pyrene-7,8-diol-9,10-epoxide adducts measured in blood, oral lining cells, or bladder lining cells. There was also no increase in mRNA or enzymatic activity of phase II enzymes and no change in glutathione levels. Thus, despite moderate drug-related toxicity, there was no significant effect on pharmacodynamic or surrogate risk biomarkers. Other agents with lower toxicity and greater activity to induce phase II enzymes are needed to definitively test the detoxification-induction paradigm in smokers.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMed2005

Relationships between cigarette consumption and biomarkers of tobacco toxin exposure.

Epidemiologic studies show a dose-response relationship between cigarettes per day and health outcomes such as heart and lung disease, and health outcomes are related to some biomarkers of tobacco exposure. The objective of this study was to examine the relationships between cigarettes per day and levels of selected biomarkers of tobacco toxin exposure: carbon monoxide (CO), metabolites of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and polycyclic aromatic hydrocarbons [total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and 1-hydroxypyrene (1-HOP), respectively], and total cotinine (cotinine plus cotinine-N-glucuronide). We did a cross-sectional analysis of merged data from (a) two clinical trials and (b) two cohorts of light smokers (total n = 400). The mean age of participants was 50.4 years and the range of cigarette consumption was 1 to 100/d; however, few subjects smoked >45 cigarettes/d (n = 12). Results show that levels of the biomarkers CO, total NNAL, and total cotinine increase with an increase in the number of cigarettes smoked per day, but not in a linear fashion. 1-HOP is a less discriminating biomarker as levels are relatively stable regardless of the number of cigarettes smoked per day. There is considerable variability in toxin measurement, especially at high levels of smoking. There was a significant correlation between cigarettes per day and total NNAL, 1-HOP, total cotinine, and CO. Total NNAL was highly significantly correlated with total cotinine and CO and also significantly correlated with 1-HOP. These findings suggest that the number of cigarettes smoked per day is not necessarily a reliable measure of toxin exposure and may underestimate tobacco toxin exposure at low levels of smoking or overestimate exposure at high levels of smoking.

Biomarkers↗

PubMed2005

Analysis of total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in smokers' blood.

The sum of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL) is an excellent biomarker for uptake of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Although numerous studies have examined levels of total NNAL in the urine of people who use tobacco products, few have quantified this biomarker in blood, and the available methods used relatively large amounts of blood. A method is urgently needed for the analysis of total NNAL in blood, the fluid most commonly stored in molecular epidemiologic studies. We developed a liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method for the analysis of total NNAL in 1-mL samples of plasma. LC-ESI-MS/MS provides both high-sensitivity and structural information supporting analyte identity. The method is practical and sensitive, with a detection limit of 8 fmol total NNAL/mL plasma. Levels of total NNAL averaged 42 +/- 22 (SD) and ranged 1.7 to 88 fmol/mL plasma in 16 smokers; NNAL was not detected in the plasma of five nonsmokers. These results show that total NNAL can readily be quantified in 1-mL plasma samples.

Biomarkers↗

PubMed2005

Longitudinal study of urinary phenanthrene metabolite ratios: effect of smoking on the diol epoxide pathway.

We have proposed that urinary phenanthrene metabolites could be used in a carcinogen metabolite phenotyping approach to identify individuals who may be susceptible to cancer induction by polycyclic aromatic hydrocarbons (PAH). In support of this proposal, we have developed methods for quantitation of r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT) and phenanthrols (HOPhe) in human urine. PheT is the end product of the diol epoxide metabolic activation pathway of PAH, whereas HOPhe are considered as detoxification products. In this study, we investigated the longitudinal consistency of these metabolites over time in smokers and nonsmokers and compared their levels. Twelve smokers and 10 nonsmokers provided urine samples daily for 7 days, then weekly for 6 weeks. Levels of PheT, HOPhe, and PheT/HOPhe ratios were relatively constant in most individuals, with mean coefficients of variation ranging from 29.3% to 45.7%. There were no significant changes over time in levels of the metabolites or in ratios. These results indicate that a single urine sample should be sufficient when comparing phenanthrene metabolites in different groups. PheT/HOPhe ratios were significantly higher in smokers than in nonsmokers, showing that smoking induces the diol epoxide metabolic activation pathway of phenanthrene. This finding is consistent with previous studies indicating that inducibility of PAH metabolism contributes to cancer risk in smokers.

Adult↗

PubMed2004

Evaluation of carcinogen exposure in people who used "reduced exposure" tobacco products.

BACKGROUND: Although tobacco products with reportedly reduced carcinogen content are being marketed, carcinogen uptake in people who use these products has not been assessed systematically. METHODS: Between June 2001 and November 2002, 54 users of smokeless tobacco and 51 cigarette smokers were randomly assigned to one of two groups. One used test products (Swedish snus for users of smokeless tobacco or OMNI cigarettes for smokers), while the other quit and used medicinal nicotine (the nicotine patch). All participants were assessed for urinary levels of total NNAL [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronide], metabolites of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Smokers were also assessed for levels of 1-hydroxypyrene (1-HOP), a biomarker of polycyclic aromatic hydrocarbon uptake. Assessments were made weekly during 2 weeks of baseline normal tobacco use and 4 weeks of treatment. Statistical tests were two-sided. RESULTS: Primary data analyses were conducted on 41 users of smokeless tobacco and 38 cigarette smokers who met the inclusion criteria. Total NNAL levels were statistically significantly lower in users of smokeless tobacco after they switched to snus or to nicotine patch (P<.001 for both groups) than they were before the switch, although the overall mean total NNAL level among subjects who used the nicotine patch was statistically significantly lower than that among those who used snus (mean = 1.2 and 2.0 pmol of NNAL/mg of creatinine, respectively; mean difference = 0.9 pmol of NNAL/mg of creatinine, 95% confidence interval [CI] = 0.2 to 1.5; P =.008). Compared with baseline levels, total NNAL levels (P =.003), but not 1-HOP levels, were statistically significantly reduced in cigarette smokers who switched to the OMNI cigarette, although both total NNAL levels and 1-HOP levels were statistically significantly reduced in smokers who switched to the nicotine patch (P<.001 for both). The overall mean total NNAL levels among smokers who used the nicotine patch was statistically significantly lower than that among smokers who used the OMNI cigarette (mean = 1.2 and 1.9 pmol of NNAL/mg of creatinine, respectively; mean difference = 0.6 pmol of NNAL/mg of creatinine, 95% CI = 0.1 to 1.1; P =.022). CONCLUSION: Switching to reduced-exposure tobacco products or medicinal nicotine can decrease levels of tobacco-associated carcinogens, with greater reductions being observed with medicinal nicotine. Medicinal nicotine is a safer alternative than modified tobacco products.

Administration, Cutaneous↗

PubMed2004

Effects of reduced cigarette smoking on the uptake of a tobacco-specific lung carcinogen.

BACKGROUND: Limited data are available on carcinogen uptake in smokers who reduce their smoking. To determine whether reducing the number of cigarettes smoked per day would lead to a corresponding reduction in carcinogen uptake, we measured levels of metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the urine of smokers who reduced their smoking for up to 26 weeks. METHODS: We recruited 153 smokers, of whom 151 were randomly assigned to a reduction group or a waitlist group. In the reduction group of 102 smokers, we measured the metabolites 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (NNAL-Gluc) at two baseline times and at weeks 4, 6, 8, 12, and 26 after baseline. Smokers were then expected to reduce their number of cigarettes per day by 25% in weeks 0-2, 50% in weeks 2-4, and 75% in weeks 4-6 and to maintain the reduced level through week 26. In the waitlist group of 49 smokers, four baseline measurements over 7 weeks were made to assess the longitudinal stability of the metabolite measurements, and then the smokers began the reduction program. All statistical tests were two-sided. RESULTS: For waitlist and reduction groups results were comparable. Statistically significant reductions in the lung carcinogen metabolites were observed at most intervals as smokers reduced the number of cigarettes smoked each day. However, the observed decreases were generally modest, always proportionally less than the reductions in cigarettes smoked per day, and sometimes transient. For example, among the 65 individuals in the reduction group who reduced cigarettes per day by 40% or more during weeks 4-12 after baseline, mean decreases in cigarettes per day were 53% (week 4), 74% (week 6), 75% (week 8), and 74% (week 12); whereas the corresponding mean reductions in NNAL plus NNAL-Gluc were 29%, 33%, 37%, and 29%. (P<.001 for all NNAL plus NNAL-Gluc values) CONCLUSIONS: Statistically significant reductions in levels of urinary metabolites of a tobacco-specific lung carcinogen were achieved by reduction in smoking, but for most smokers, reductions were modest and transient.

Adult↗