RESUMEN
BACKGROUND: The prevalence of tobacco use, both cigarette smoking and smokeless, including iqmik (homemade smokeless tobacco prepared with dried tobacco leaves mixed with alkaline ash), and of tobacco-related cancer is high in Alaskan Native people (AN). To investigate possible mechanisms of increased cancer risk we studied levels of nicotine and tobacco-specific nitrosamines (TSNA) in tobacco products and biomarkers of tobacco toxicant exposure in Southwestern AN people. METHODS: Participants included 163 cigarette smokers, 76 commercial smokeless tobacco, 20 iqmik, 31 dual cigarette smokers and smokeless tobacco, and 110 nontobacco users. Tobacco use history, samples of tobacco products used, and blood and urine samples were collected. RESULTS: Nicotine concentrations were highest in cigarette tobacco and TSNAs highest in commercial smokeless tobacco products. The AN participants smoked on average 7.8 cigarettes per day. Nicotine exposure, assessed by several biomarker measures, was highest in iqmik users, and similar in smokeless tobacco and cigarette smokers. TSNA exposure was highest in smokeless tobacco users, and polycyclic aromatic hydrocarbon exposure was highest in cigarette smokers. CONCLUSIONS: Despite smoking fewer cigarettes per day, AN cigarette smokers had similar daily intake of nicotine compared to the general U.S. population. Nicotine exposure was greatest from iqmik, likely related to its high pH due to preparation with ash, suggesting high addiction potential compared to other smokeless tobacco products. TSNA exposure was much higher with smokeless tobacco than other product use, possibly contributing to the high rates of oral cancer. IMPACT: Our data contribute to an understanding of the high addiction risk of iqmik use and of the cancer-causing potential of various forms of tobacco use among AN people.
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Carcinógenos/metabolismo , Indígenas Norteamericanos , Nicotiana , Nicotina/metabolismo , Fumar/etnología , Fumar/metabolismo , Tabaco sin Humo/metabolismo , Adulto , Alaska , Femenino , Humanos , Masculino , Fumar/efectos adversos , Tabaco sin Humo/efectos adversosRESUMEN
This research describes the development and validation of a biorelevant in vitro release/permeation system to predict the in vivo performance of oral transmucosal dosage forms. The system is a biorelevant bidirectional transmucosal apparatus which allows better simulation of oral cavity physiological variables in comparison to compendial dissolution apparatuses and therefore may be a better predictor of in vivo behavior. The feasibility of the bidirectional apparatus was studied using smokeless tobacco (snus) as a model oral transmucosal product. In this research, nicotine release and permeation was investigated from commercially available snus using a modified USP IV flow-through apparatus, a commercially available vertical diffusion cell and a fabricated novel bidirectional transmucosal apparatus. The percent nicotine released/permeated was utilized as an input function for the prediction of in vivo plasma nicotine profiles by back calculation based on the Wagner-Nelson method. The prediction errors in C(max) and AUC(0-∞) with the USP IV flow-through device, vertical diffusion cell and novel apparatus were 4.03, 22.85 and 1.59 and -5.85, 5.85 and -9.27% respectively. This work demonstrated the suitability of the novel bidirectional transmucosal apparatus for predicting the in vivo behavior of oral transmucosal products.
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Membranas Artificiales , Mucosa Bucal/metabolismo , Nicotina/metabolismo , Agonistas Nicotínicos/metabolismo , Tecnología Farmacéutica/instrumentación , Tabaco sin Humo/metabolismo , Administración Bucal , Adsorción , Adulto , Área Bajo la Curva , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Difusión , Formas de Dosificación , Composición de Medicamentos , Diseño de Equipo , Estudios de Factibilidad , Humanos , Modelos Biológicos , Nicotina/administración & dosificación , Nicotina/sangre , Nicotina/farmacocinética , Agonistas Nicotínicos/administración & dosificación , Agonistas Nicotínicos/sangre , Agonistas Nicotínicos/farmacocinética , Permeabilidad , Reproducibilidad de los Resultados , Saliva/metabolismo , Solubilidad , Tecnología Farmacéutica/métodos , Tabaco sin Humo/farmacocinéticaRESUMEN
BACKGROUND: Tobacco use is highly prevalent in India, with almost half of adult men consuming tobacco in either smoke or smokeless forms (particularly chewing). Although cigarette smoking is known to produce acute hemodynamic effects, there is a lack of data concerning such effects of chewing tobacco. OBJECTIVE: The aim of this study was to determine the acute hemodynamic and coronary vasomotor effects of chewing tobacco. METHODS: Twelve habitual tobacco chewers (mean ± SD age 51.3 ± 6.9 years) undergoing elective coronary angiography were included in the study. Following coronary angiography, a 7F thermodilution Swan Ganz continuous cardiac output pulmonary artery catheter was used to continuously measure the right heart pressures and cardiac output. Having obtained baseline hemodynamic data, 1g of tobacco was given to be chewed. Subsequently, hemodynamic data were obtained periodically over a period of 60 minutes. A repeat left coronary injection was performed, 10 minutes after giving the tobacco, in the right anterior oblique view to estimate the diameter of the left anterior descending (LAD) artery by quantitative coronary angiography. RESULTS: Chewing tobacco led to a significant acute increase in heart rate (from 68.3 ± 12.4 beats/min to 80.6 ± 14.6 beats/min, peaking at 10 minutes) and cardiac output (from 3.8 ± 0.45 L/min to 4.7 ± 0.64 L/min, peaking at 15 minutes). There were no significant changes in the right atrial, pulmonary artery, or wedge pressures and hence no change in the pulmonary vascular resistance. More importantly, chewing tobacco was associated with coronary vasoconstriction (proximal LAD diameter change from 3.17 ± 0.43 mm to 2.79 ± 0.37 mm; p-value 0.02; mid LAD diameter change from 2.75 ± 0.36 mm to 2.40 ± 0.22 mm; p-value 0.03). CONCLUSION: Chewing smokeless tobacco leads to coronary vasoconstriction and also produces significant hemodynamic alterations. These changes may have a bearing on excess vascular disease.
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Circulación Coronaria/fisiología , Hemodinámica/fisiología , Circulación Pulmonar/fisiología , Tabaco sin Humo/efectos adversos , Vasoconstricción/fisiología , Adulto , Circulación Coronaria/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Circulación Pulmonar/efectos de los fármacos , Factores de Tiempo , Tabaquismo/etiología , Tabaquismo/fisiopatología , Tabaco sin Humo/metabolismo , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
Assessment of biomarkers is an appropriate way to estimate exposure to cigarette mainstream smoke and smokeless tobacco (SLT) constituents in tobacco consumers. Using the US National Health and Nutrition Examination Survey (NHANES, 1999-2008), biomarkers of volatile organic compounds, halogenated aromatic hydrocarbons (HAHs), polycyclic aromatic hydrocarbons (PAHs), acrylamide, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and metals were evaluated. In general, biomarker levels in SLT consumers were significantly lower than in smokers (excluding NNK and some HAHs) and were not significantly different compared with nonconsumers (excluding NNK and some PAHs). These results provide useful information for science-based risk assessment and regulation of tobacco products.
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Cotinina/sangre , Encuestas Nutricionales , Fumar/sangre , Tabaco sin Humo/metabolismo , Adulto , Anciano , Biomarcadores/sangre , Biomarcadores/orina , Butanonas/orina , Femenino , Humanos , Hidrocarburos Halogenados/sangre , Masculino , Metales/sangre , Metales/orina , Persona de Mediana Edad , Hidrocarburos Policíclicos Aromáticos/orina , Fumar/orina , Compuestos Orgánicos Volátiles/sangre , Adulto JovenRESUMEN
Consumption of nicotine in the form of smokeless tobacco (snus, snuff, chewing tobacco) or nicotine-containing medication (gum, patch) may benefit sport practice. Indeed, use of snus seems to be a growing trend and investigating nicotine consumption amongst professional athletes is of major interest to sport authorities. Thus, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the detection and quantification of nicotine and its principal metabolites cotinine, trans-3-hydroxycotinine, nicotine-N'-oxide and cotinine-N-oxide in urine was developed. Sample preparation was performed by liquid-liquid extraction followed by hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS/MS) operated in electrospray positive ionization (ESI) mode with selective reaction monitoring (SRM) data acquisition. The method was validated and calibration curves were linear over the selected concentration ranges of 10-10,000 ng/mL for nicotine, cotinine, trans-3-hydroxycotinine and 10-5000 ng/mL for nicotine-N'-oxide and cotinine-N-oxide, with calculated coefficients of determination (R(2)) greater than 0.95. The total extraction efficiency (%) was concentration dependent and ranged between 70.4 and 100.4%. The lower limit of quantification (LLOQ) for all analytes was 10 ng/mL. Repeatability and intermediate precision were ≤9.4 and ≤9.9%, respectively. In order to measure the prevalence of nicotine exposure during the 2009 Ice Hockey World Championships, 72 samples were collected and analyzed after the minimum of 3 months storage period and complete removal of identification means as required by the 2009 International Standards for Laboratories (ISL). Nicotine and/or metabolites were detected in every urine sample, while concentration measurements indicated an exposure within the last 3 days for eight specimens out of ten. Concentrations of nicotine, cotinine, trans-3-hydroxycotinine, nicotine-N'-oxide and cotinine-N-oxide were found to range between 11 and 19,750, 13 and 10,475, 10 and 8217, 11 and 3396, and 13 and 1640 ng/mL, respectively. When proposing conservative concentration limits for nicotine consumption prior and/or during the games (50 ng/mL for nicotine, cotinine and trans-3-hydroxycotinine and 25 ng/mL for nicotine-N'-oxide and cotinine-N-oxide), about half of the hockey players were qualified as consumers. These findings significantly support the likelihood of extensive smokeless nicotine consumption. However, since such conclusions can only be hypothesized, the potential use of smokeless tobacco as a doping agent in ice hockey requires further investigation.
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Cromatografía Liquida/métodos , Nicotina/metabolismo , Nicotina/orina , Espectrometría de Masas en Tándem/métodos , Tabaco sin Humo/análisis , Cromatografía Liquida/instrumentación , Hockey , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Tabaco sin Humo/metabolismoRESUMEN
INTRODUCTION: Potential-reduced exposure products (PREPs) are marketed as a way for smokers to continue using tobacco while possibly lessening their tobacco toxicant intake. Some tobacco-based PREPs are combustible and intended to be smoked, while others are noncombustible and intended to be administered orally (e.g., Camel Snus [CS] tobacco sachets and Ariva tobacco tablets). The ability of these noncombustible PREPs to reduce smokers' exposure to cigarette-delivered toxicants and suppress tobacco abstinence symptoms effectively is unclear. Clinical laboratory methods have been used to measure combustible PREP-associated toxicant exposure and abstinence symptom suppression and could be applied to evaluating the effects of orally administered noncombustible PREPs. METHODS: In this study, 21 smokers (6 women) participated in four 5-day conditions that differed by product used: CS, Ariva, own brand cigarettes, or no tobacco. Measures included expired-air carbon monoxide (CO), the urinary metabolite of nicotine (cotinine), the urinary metabolite of the carcinogen NNK (NNAL-T), and subjective effect ratings. RESULTS: Relative to own brand, all other conditions were associated with CO and cotinine levels that were lower and abstinence symptom ratings that were greater. Only no-tobacco use was associated with significantly lower NNAL levels. Acceptability ratings were also lower in all conditions relative to own brand. DISCUSSION: Although these oral products reduce exposure to CO, their ineffective abstinence symptom suppression and low acceptability may limit their viability as PREPs. As with combustible PREPs, clinical laboratory study of orally administered noncombustible PREPs will be a valuable part of any comprehensive PREP evaluation strategy.
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Cese del Hábito de Fumar/métodos , Tabaco sin Humo/metabolismo , Administración Oral , Adolescente , Adulto , Monóxido de Carbono/análisis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nicotina/orina , Nitrosaminas/orina , Tabaco sin Humo/farmacocinética , Adulto JovenRESUMEN
N'-nitrosonornicotine (NNN) is a strong carcinogen present in unburned tobacco and cigarette smoke. We here analyze data obtained in two studies, in which a biomarker of exposure to NNN--the sum of NNN and its pyridine-N-glucuronide, called total NNN--was quantified in the urine of people who had stopped smoking and used various nicotine replacement therapy (NRT) products. In 13 of 34 nicotine gum or lozenge users from both studies, total NNN at one or more time points after biochemically confirmed smoking cessation was comparable with, or considerably higher than, the baseline levels. For most of the subjects who used the nicotine patch as a smoking cessation aid, urinary total NNN at all post-quit time points was <37% of their mean baseline levels. These results indicate that endogenous formation of significant amounts of NNN may occur sporadically in some users of oral NRT. Given the carcinogenicity of NNN and the frequent use of nicotine gum as a smoking cessation aid, further studies are needed so that preventive measures can be developed.
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Carcinógenos/metabolismo , Nitrosaminas/orina , Cese del Hábito de Fumar , Fumar/orina , Tabaco sin Humo/metabolismo , Biomarcadores/orina , Humanos , Nicotina/administración & dosificación , Prevención del Hábito de FumarRESUMEN
INTRODUCTION: Nitrosation of nicotine or its metabolites in the human body could lead to formation of the 2 carcinogenic tobacco-specific nitrosamines-N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). METHODS: We investigated the possibility of endogenous formation of NNN in people who had stopped smoking and used the 21-mg nicotine patch for 6 months. We quantified urinary biomarkers of exposure to NNN-the sum of NNN and its pyridine-N-glucuronide, referred to as total NNN. Also measured were NNK metabolites-the sum of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its N- and O-glucuronides, referred to as total NNAL. RESULTS: The average decline of urinary total NNN was less drastic than that of total NNAL: 22% of baseline total NNN and 7.3% of baseline total NNAL were detected in urine 24 weeks after smoking cessation and patch use (p = .02). The average ratio of total NNN to total NNAL in the same urine samples increased from 0.14 in baseline urine to 0.38 after 24 weeks of nicotine patch use. DISCUSSION: Overall, these results demonstrate that endogenous formation of NNN may occur in nicotine patch users. However, the levels of urinary total NNN during patch use were generally extremely low. Moreover, in 10 of 20 subjects analyzed here, the rate of decline in total NNN was similar to that in total NNAL, indicating that endogenous formation of NNN is virtually nonexistent in these subjects. Supplementation with ascorbic acid could be a simple approach to block possible NNN formation in nicotine patch users.
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Carcinógenos/metabolismo , Nitrosaminas/orina , Fumar/orina , Tabaco sin Humo/metabolismo , Administración Cutánea , Adulto , Biomarcadores/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nicotina/administración & dosificación , Nicotina/uso terapéutico , Prevención del Hábito de Fumar , Factores de TiempoRESUMEN
Several potential reduced exposure products (PREPs) for smokeless tobacco (SLT) users are marketed in the United States, though their effects are largely unknown. These products include some that are low in tobacco-specific nitrosamines (TSNs), like Stonewall, a pressed tobacco tablet, and General snus, a moist snuff product produced in Sweden. Methodology assessing the toxicant exposure and effects of cigarette-like PREPs for smokers has been developed, and might be modified for use in evaluating PREPs for SLT users. This report describes two studies examining the toxicant exposure and effects of two PREPs for SLT users. Study 1 (n = 13) consisted of four 4.5-hr laboratory sessions where SLT products (own brand, Stonewall, General snus, and tobacco-free placebo) were used for four 30-min episodes and nicotine exposure and tobacco/nicotine abstinence symptoms were measured. Study 2 (n = 19) consisted of four 5-day ad libitum use periods when participants used own brand, Stonewall, General snus, or no SLT and urinary levels of metabolites of nicotine (cotinine) and the TSN 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNAL) and abstinence symptoms were measured. Compared with own brand, Stonewall was associated with lower levels of cotinine and NNAL, while General snus was associated with similar levels of cotinine and lower levels of NNAL. Abstinence symptoms generally did not differ across tobacco conditions. These results show that clinical laboratory methods can be used to evaluate the toxicant exposure and abstinence symptom suppression associated with PREPs for SLT users.
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Carcinógenos/análisis , Monitoreo del Ambiente , Reducción del Daño , Nicotina/análisis , Cese del Uso de Tabaco/métodos , Tabaco sin Humo/metabolismo , Adulto , Biomarcadores/sangre , Biomarcadores/orina , Monóxido de Carbono/metabolismo , Cotinina/sangre , Cotinina/orina , Femenino , Humanos , Exposición por Inhalación/análisis , Masculino , Persona de Mediana Edad , Nitrosaminas/sangre , Nitrosaminas/orinaRESUMEN
This preliminary study examined the effects of tobacco-free snuff (intervention, n = 52) compared with no snuff (control, n = 54) for reducing tobacco use among smokeless tobacco (ST) users not interested in quitting. Both groups received behavioral instructions, and intervention subjects received tobacco-free snuff for 8 weeks. Participants were required to reduce their intake by 50% during the first 4 weeks and by 75% during the subsequent 4 weeks. Follow-up occurred at 12 weeks. Significant reductions were observed from baseline to week 8 (end of treatment) for both treatment groups in the amount of ST use (tins/week and dips/day, p<.001); mean urinary cotinine (p<.001); and mean urinary total NNAL, a carcinogen biomarker (p<.001). At week 8 the intervention resulted in a lower mean total NNAL (p = .048). Compared with the control condition, the intervention resulted in a higher percentage of subjects achieving at least a 50% reduction in cotinine (p = .046) and total NNAL (p = .002) at the end of treatment, more quit attempts (p = .030), and a longer mean duration of abstinence (p = .013) through follow-up. An ST reduction intervention incorporating tobacco-free snuff could potentially reduce risk for ST-related disease beyond that achieved with no snuff by increasing the number of patients who achieve significant reductions in carcinogen exposure and, more important, by facilitating tobacco abstinence by increasing quit attempts and abstinence duration.
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Prevención del Hábito de Fumar , Fumar/orina , Tabaquismo/terapia , Tabaquismo/orina , Tabaco sin Humo/clasificación , Administración Oral , Adulto , Carcinógenos/metabolismo , Cotinina/orina , Femenino , Estudios de Seguimiento , Humanos , Masculino , Nitrosaminas/orina , Proyectos de Investigación , Tabaco sin Humo/metabolismo , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate erythrocyte malondialdehyde (MDA) levels and activities of superoxide dismutase (SOD) and glutathione reductase (GR) in tobacco chewers, in view of possible oxidative stress in oral smokeless tobacco. MATERIAL AND METHODS: Sixty healthy male tobacco chewers, aged 30.6+/-4.7 years with a 3 to 10-year (7.37+/-2.1) history of tobacco chewing, were included in the study. Thirty-two healthy male volunteers, aged 26.5+/-4.8 years, served as controls. All the participants were from the same community and of similar dietary habits. RESULTS: The erythrocyte MDA level and activities of erythrocyte SOD and GR were estimated. There was a significant duration- (tobacco chewing) dependent increase in erythrocyte MDA levels along with a significant duration- (tobacco chewing) dependent decrease in erythrocyte SOD and GR activity. CONCLUSION: Oral smokeless tobacco causes a duration-dependent increase in oxidative stress.
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Estrés Oxidativo , Tabaco sin Humo/efectos adversos , Tabaco sin Humo/metabolismo , Adulto , Estudios de Casos y Controles , Eritrocitos/metabolismo , Glutatión Reductasa/metabolismo , Humanos , Peroxidación de Lípido , Masculino , Malondialdehído/sangre , Superóxido Dismutasa/metabolismoRESUMEN
Tobacco-specific nitrosamines are believed to play a significant role as causes of cancer in people who use tobacco products. Whereas the uptake of one tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, has been shown by analysis of its metabolites in urine, there are no published studies on urinary levels of N'-nitrosonornicotine (NNN), N'-nitrosoanatabine (NAT), and N'-nitrosoanabasine (NAB) or their metabolites in human urine. We developed a method for quantitation of NNN, NAT, NAB, and their pyridine-N-glucuronides NNN-N-Gluc, NAT-N-Gluc, and NAB-N-Gluc in human urine. Total NNN (NNN plus NNN-N-Gluc) was assayed using 5-methyl-N'-nitrosonornicotine as internal standard. Urine was treated with beta-glucuronidase. Following solvent partitioning and solid-phase extraction, total NNN was determined using gas chromatography with nitrosamine-selective detection. Total NAT and total NAB were quantified in the same samples. Separate quantitation of NNN and NNN-N-Gluc was accomplished by extraction of the urine with ethyl acetate before beta-glucuronidase hydrolysis; NNN was analyzed in the ethyl acetate extract, and after enzyme treatment, NNN released from NNN-N-Gluc was quantified in the extracted urine. Separate analyses of NAT, NAT-N-Gluc, NAB, and NAB-N-Gluc proceeded similarly. Analyte identities were confirmed by gas chromatography-tandem mass spectrometry. Mean levels of total NNN, NAT, and NAB in the urine of 14 smokers were (pmol/mg creatinine) 0.18 +/- 0.22, 0.19 +/- 0.20, and 0.040 +/- 0.039, respectively, whereas the corresponding amounts in the urine of 11 smokeless tobacco users were 0.64 +/- 0.44, 1.43 +/- 1.10, and 0.23 +/- 0.19, respectively. Pyridine-N-glucuronides accounted for 59% to 90% of total NNN, NAT, and NAB. The results of this study show the presence of NNN, NAT, NAB, and their pyridine-N-glucuronides in human urine and provide a quantitative method for application in mechanistic and epidemiologic studies of the role of tobacco-specific nitrosamines in human cancer.
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Carcinógenos/metabolismo , Cromatografía de Gases/métodos , Glucurónidos/orina , Nitrosaminas/orina , Fumar/orina , Tabaco sin Humo/metabolismo , Animales , Cotinina/orina , Creatinina/orina , HumanosRESUMEN
AIM: To study exposure to nicotine in breastfed infants in relation to parental smoking habits. MATERIAL AND METHODS: Forty mother-infant pairs were studied. Twenty non-smoking mothers, 18 smoking (2-20 cigarettes per day) and two snuff-taking mothers were included. All infants were healthy, exclusively breastfed and their postnatal age was 6 wk. During a home visit, parental smoking habits were recorded, and the time of mothers' last smoke or taking of snuff and breastfeeding were recorded. Breast milk and infant urine samples were collected. Concentrations of nicotine and cotinine were analysed with gas chromatography. The amount of milk ingested during the home visit was calculated by weighing the infants. RESULTS: Two non-smoking and non-snuff-taking women had milk containing nicotine (28 and 13 microg/l, respectively). Both had smoking spouses. In the smoking and snuff-taking group, the mean (SD) milk nicotine concentration was 44 (38) microg/l (n = 36). When milk samples taken 7 h and 0.6 h after smoking were compared, the concentration of milk nicotine increased from 21 to 51 microg/l (p < 0.01). The two snuff-taking mothers exposed their children to higher milk nicotine concentrations than all but two of the smokers. The concentrations of the metabolite cotinine in infant urine correlated with the dose of nicotine ingested during the home visit (r = 0.84, p < 0.01). CONCLUSIONS: Breastfed infants with a smoking or snuff-taking mother are exposed to nicotine in breast milk. The mean intake of nicotine via milk is 7 microg/kg/d. With a shorter time between the mothers' smoking and breastfeeding, the milk nicotine concentration will increase. Both passive smoking at home and snuff-taking were associated with measurable nicotine levels in milk. Healthcare personnel promoting breastfeeding should be aware of these factors influencing exposure to nicotine in the breastfed infant.
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Leche Humana/química , Nicotina/metabolismo , Fumar , Cotinina/orina , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Nicotina/farmacología , Suecia , Tabaco sin Humo/metabolismo , Aumento de Peso/efectos de los fármacosRESUMEN
Normal salivary function is considered to be critical for the maintenance of healthy oral mucosa. Oral fluids provide an easily available non-invasive for the diagnosis of a wide range of diseases and clinical situations. The present study evaluated the variations in the biochemical constituents of saliva of leukoplakia and oral cancer patients when compared with that of the control group. 90 individuals were grouped into 6 categories with 15 individuals in each group. The groups included individuals without tobacco or alcohol habits, tobacco smokers, tobacco chewers, alcohol consumers, leukoplakia and oral cancer patients. There was significant alteration in the salivary biochemical composition of leukoplakia and oral cancer patients which could be attributed to the impairment of salivary gland function caused by tobacco and alcohol usage or by the disease process itself.
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Consumo de Bebidas Alcohólicas/metabolismo , Carcinoma de Células Escamosas/química , Leucoplasia Bucal/química , Neoplasias de la Boca/química , Saliva/química , Fumar/metabolismo , Tabaco sin Humo/metabolismo , Adulto , Amilasas/análisis , Femenino , Humanos , Concentración de Iones de Hidrógeno , Masculino , Persona de Mediana Edad , Potasio/análisis , Proteínas y Péptidos Salivales/análisis , Sodio/análisis , Estadística como AsuntoRESUMEN
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a tobacco-specific lung carcinogen which may play an important role as a cause of lung cancer in smokers. NNK is extensively metabolized to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which like NNK is a potent pulmonary carcinogen. NNAL in turn is glucuronidated, and both NNAL and its glucuronides are excreted in human urine. Previous studies have clearly demonstrated the presence in human urine of 4-(methylnitrosamino)-1-(3-pyridyl)-1-(O-beta-D-glucopyranuronosyl)butane (NNAL-O-Gluc), but did not exclude the presence of 4-(methylnitrosamino)-1-(3-pyridyl-N-beta-D-glucopyranuronosyl)-1-butanolonium inner salt (NNAL-N-Gluc). In this study, we quantified NNAL, NNAL-N-Gluc, and NNAL-O-Gluc in the urine of smokers, snuff-dippers, and people who used the oral tobacco product "toombak". The presence of NNAL-N-Gluc in the urine of toombak users was confirmed by LC-ESI-MS/MS. In smokers' urine, NNAL-N-Gluc, NNAL-O-Gluc, and NNAL comprised (mean +/- SD) 26.5 +/- 6.2, 32.1 +/- 17.6, and 41.4 +/- 16.6%, respectively, of total NNAL. In snuff-dippers' urine, the corresponding figures were 13.6 +/- 5.1, 46.6 +/- 11.7, and 36.6 +/- 9.3%. NNAL-N-Gluc comprised 50 +/- 25% of total glucuronidated NNAL in smokers and 24 +/- 12% in snuff-dippers. This difference was significant (P = 0.01), suggesting that smoking induces glucuronidation of NNAL. The results of this study demonstrate that NNAL-N-Gluc contributes substantially to NNAL-glucuronides in human urine. These results are important for a clearer understanding of mechanisms of detoxification of NNK in humans.
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Carcinógenos/análisis , Glucuronatos/orina , Nitrosaminas/orina , Carcinógenos/clasificación , Glucuronatos/clasificación , Humanos , Nitrosaminas/clasificación , Plantas Tóxicas , Fumar/orina , Tabaco sin Humo/metabolismoRESUMEN
Two major metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were previously shown to be highly persistent in human urine after cessation of cigarette smoking. We hypothesized that NNK or its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), was sequestered in the lung. In this study, we further evaluated this hypothesis by quantifying the NNK metabolites, NNAL and its glucuronides (NNAL-Gluc), in urine and plasma after cessation of smokeless tobacco use, in which NNK is administered p.o. rather than by inhalation. Thirteen male nonsmokers, 11 snuff dippers and 2 tobacco chewers, participated in the study. Urine and plasma were obtained at baseline and at intervals 2-126 days after cessation of smokeless tobacco use. The distribution half-lives t(1/2alpha) (days) of NNAL (1.32 +/- 0.85 versus 3.35 +/- 1.86) and NNAL-Gluc (1.53 +/- 1.22 versus 3.89 +/- 2.43) were significantly shorter in smokeless tobacco users than in smokers. There were no significant differences in the terminal half-lives t(1/2beta) (days) of NNAL (26.3 +/- 16.7 versus 45.2 +/- 26.9) and NNAL-Gluc (26.1 +/- 15.1 versus 39.6 +/- 26.0) in smokeless tobacco users and smokers. Baseline levels as well as renal clearance of the NNK metabolites correlated with number of tins or pouches of smokeless tobacco consumed. Ratios of (S)-NNAL:(R)-NNAL and (S)-NNAL-Gluc:(R)-NNAL-Gluc in urine were significantly (3.1-5.7 times) higher 7 days after cessation than at baseline in both smokeless tobacco users and smokers, indicating stereoselective retention of (S)-NNAL. Collectively, the results of this study suggest that there is a receptor in the human body, possibly in the lung, for (S)-NNAL, the more carcinogenic NNAL enantiomer. These data may have considerable implications for understanding mechanisms of tumor induction by NNK.
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Glucuronatos/orina , Nitrosaminas/metabolismo , Nitrosaminas/orina , Cese del Uso de Tabaco , Tabaco sin Humo/metabolismo , Administración Oral , Adulto , Glucuronatos/sangre , Glucuronatos/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Nitrosaminas/sangre , Nitrosaminas/farmacocinética , Tabaco sin Humo/farmacocinéticaAsunto(s)
Consumo de Bebidas Alcohólicas , Pruebas Respiratorias , Etanol/análisis , Plantas Tóxicas , Tabaco sin Humo/farmacología , Pruebas Respiratorias/métodos , Etanol/metabolismo , Etanol/farmacocinética , Femenino , Medicina Legal , Humanos , Masculino , Tabaco sin Humo/metabolismo , Tabaco sin Humo/farmacocinéticaRESUMEN
Commercial moist snuff products are used by placing a portion of tobacco inside the mouth between the inner cheek or lip and gum. Nicotine is absorbed into the blood stream via transfer across various oral membranes including the buccal mucosa (cheek lining). The resulting salivary pH when a given moist snuff product is placed in the mouth is an important factor for nicotine absorption because it will affect the proportion of free base nicotine that is readily available for absorption. The resulting salivary pH for a given moist snuff product will be determined in part by the relative acid-base buffering capacities of the saliva and moist snuff, as well as the pHs of the saliva and moist snuff prior to coming in contact with one another. In the current study, the acid-base buffering capacities (mu eq/g) of a series of commercial moist snuff products were determined and compared to the acid-base buffering capacity for unstimulated, whole human saliva. The buffering capacities of the moist snuff products were determined to be 10-20 times higher than the buffering capacity of human saliva. The resulting salivary pH ranges after contact between an artifical saliva and the various moist snuff products were also determined; the results were used to predict the proportion of free base nicotine that can be expected to occur in the mouth during the first few minutes of product use. These studies provide a basis for examining and understanding the effects that moist snuff product pHs and buffering capacities may be expected to have on nicotine absorption.
Asunto(s)
Nicotina/farmacocinética , Plantas Tóxicas , Saliva/metabolismo , Tabaco sin Humo/metabolismo , Absorción , Adulto , Tampones (Química) , Femenino , Humanos , Concentración de Iones de Hidrógeno , Masculino , Persona de Mediana EdadRESUMEN
People who use tobacco products are exposed to considerable amounts of N'-nitrosonornicotine (NNN), a well-established esophageal carcinogen in rats. NNN is believed to play a significant role as a cause of esophageal and oral cavity cancer in smokers and snuff dippers. The carcinogenicity of NNN is dependent on its metabolic activation. However, virtually all studies carried out to date on NNN metabolism have used racemic material. In this study, we examined the metabolism of [5-(3)H]-(S)-NNN and [5-(3)H]-(R)-NNN in cultured rat esophagus and in vivo in rats. Cultured rat esophagus metabolized (S)-NNN (1 microM) predominantly to products of 2'-hydroxylation, 4-oxo-4-(3-pyridyl)butanoic acid (keto acid) and 4-hydroxy-1-(3-pyridyl)-1-butanone (keto alcohol). In contrast, the major metabolite of (R)-NNN under these conditions was 4-hydroxy-4-(3-pyridyl)butanoic acid (hydroxy acid), a product of NNN 5'-hydroxylation. The 2'-hydroxylation:5'-hydroxylation metabolite ratio ranged from 6.22 to 8.06 at various time intervals in the incubations with (S)-NNN, while the corresponding ratios were 1.12-1.33 in the experiments with (R)-NNN. These differences were statistically significant (P<0.001). Since 2'-hydroxylation is believed to be the major metabolic activation pathway of NNN in the rat esophagus, the results demonstrate that (S)-NNN is metabolically activated more extensively than (R)-NNN in this tissue, and therefore may be more carcinogenic. Rats were treated with 0.3 mg/kg of [5-(3)H]-(R)-NNN, [5-(3)H]-(S)-NNN, or racemic [5-(3)H]NNN by gavage, and the urinary metabolites were analyzed. The major metabolites were hydroxy acid and keto acid. As in the in vitro studies, products of 2'-hydroxylation predominated in the urine of the rats treated with (S)-NNN while products of 5'-hydroxylation were more prevalent in the rats treated with (R)-NNN. 2'-Hydroxylation:5'-hydroxylation metabolite ratios ranged from 1.66 to 2.04 in the urine at various times after treatment with (S)-NNN, while the ratios were 0.398-0.450 for the rats treated with (R)-NNN (P<0.001). The results of this study provide new insights into NNN metabolism in rats and suggest that the carcinogenicity of (S)-NNN, the predominant enantiomer in tobacco products, may be greater than that of (R)-NNN or racemic NNN.
Asunto(s)
Nitrosaminas/metabolismo , Plantas Tóxicas , Tabaco sin Humo/metabolismo , Animales , Células Cultivadas , Esófago/citología , Esófago/metabolismo , Masculino , Nitrosaminas/síntesis química , Nitrosaminas/toxicidad , Ratas , Ratas Endogámicas F344 , Estereoisomerismo , Tabaco sin Humo/toxicidadRESUMEN
OBJECTIVE: The present study was undertaken to evaluate lipid profile in cigarette smokers and tobacco chewers and to see whether tobacco chewing causes same degree of alteration in lipid profile as done by smoking. METHODS: Serum lipid profile was studied in 30 smokers (Group A), 30 tobacco chewers (Group B) and 30 controls i.e., non-smokers and non-tobacco chewers (Group C). RESULTS: High density lipoprotein-cholesterol was lower both in smoker (P < 0.01) as well as in tobacco chewers (P < 0.001) than the controls. Both smokers and tobacco chewers had higher values of total cholesterol, low density lipoprotein cholesterol, very low density lipoprotein-cholesterol and, triglycerides as compared to non-smoker, non-tobacco chewer group whereas the differences in levels of lipids in smokers and tobacco chewers were not statistically significant. CONCLUSION: Though different mode of addictions, smoking and tobacco chewing have an equal and comparable adverse effects on lipid profile and therefore raising cardiovascular risk in same proportion.