Neal L Benowitz

San Francisco VA Medical Center, San Francisco, California, United States

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Publications (593)4271.02 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The highly genetically variable enzyme CYP2A6 metabolizes nicotine to cotinine (COT) and COT to trans-3'-hydroxycotinine (3HC). The nicotine metabolite ratio (NMR, 3HC/COT) is commonly used as a biomarker of CYP2A6 enzymatic activity, rate of nicotine metabolism, and total nicotine clearance; NMR is associated with numerous smoking phenotypes, including smoking cessation. Our objective was to investigate the impact of different measurement methods, at different sites, on plasma and urinary NMR measures from ad libitum smokers. Plasma (n=35) and urine (n=35) samples were sent to eight different laboratories, which employed similar and different methods of COT and 3HC measurements to derive the NMR. We used Bland-Altman analysis to assess agreement, and Pearson correlations to evaluate associations, between NMR measured by different methods. Measures of plasma NMR were in strong agreement between methods according to Bland-Altman analysis (ratios 0.82-1.16) and were highly correlated (all Pearson r>0.96, P<0.0001). Measures of urinary NMR were in relatively weaker agreement (ratios 0.62-1.71) and less strongly correlated (Pearson r values of 0.66-0.98, P<0.0001) between different methods. Plasma and urinary COT and 3HC concentrations, while weaker than NMR, also showed good agreement in plasma, which was better than in urine, as was observed for NMR. Plasma is a very reliable biological source for the determination of NMR, robust to differences in these analytical protocols or assessment site. Together this indicates a reduced need for differential interpretation of plasma NMR results based on the approach used, allowing for direct comparison of different studies. Copyright © 2015, American Association for Cancer Research.
    Cancer Epidemiology Biomarkers & Prevention 05/2015; DOI:10.1158/1055-9965.EPI-14-1381 · 4.32 Impact Factor
  • PLoS ONE 05/2015; 10(5):e0128109. DOI:10.1371/journal.pone.0128109 · 3.53 Impact Factor
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    ABSTRACT: The association between cigarette smoke exposure and the acute respiratory distress syndrome in patients with the most common acute respiratory distress syndrome risk factors of sepsis, pneumonia, and aspiration has not been well studied. The goal of this study was to test the association between biomarker-confirmed cigarette smoking and acute respiratory distress syndrome in a diverse cohort. Prospective cohort. Tertiary care center. Four hundred twenty-six critically ill patients with acute respiratory distress syndrome risk factors (excluding trauma and transfusion) INTERVENTIONS:: None. We obtained smoking histories and measured urine 4-(methylnitrosamino)-1-(3-pyridyl)-1--butanol (a biomarker of cigarette smoke exposure) on urine samples obtained at the time of study enrollment. The association between cigarette smoke exposure and acute respiratory distress syndrome differed based on acute respiratory distress syndrome risk factor (p < 0.02 for interaction). In patients with nonpulmonary sepsis as the primary acute respiratory distress syndrome risk factor (n = 212), 39% of those with acute respiratory distress syndrome were current smokers by history compared with 22% of those without acute respiratory distress syndrome (odds ratio, 2.28; 95% CI, 1.24-4.19; p = 0.008). Likewise, cigarette smoke exposure as measured by urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol was significantly associated with acute respiratory distress syndrome in this group. The increased risk of acute respiratory distress syndrome in nonpulmonary sepsis was restricted to patients with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol levels consistent with active smoking and was robust to adjustment for other acute respiratory distress syndrome predictors. Cigarette smoke exposure as measured by history or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol was not associated with acute respiratory distress syndrome in patients with other risk factors (e.g., pneumonia and aspiration). Cigarette smoking measured both by history and biomarker is associated with an increased risk of acute respiratory distress syndrome in patients with nonpulmonary sepsis. This finding has important implications for tobacco product regulation and for understanding the pathogenesis of acute respiratory distress syndrome.
    Critical care medicine 05/2015; DOI:10.1097/CCM.0000000000001089 · 6.15 Impact Factor
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    ABSTRACT: The nicotine metabolite ratio (NMR) of 3'-hydroxycotinine to cotinine is a noninvasive marker of the rate of nicotine metabolism. Fast metabolism (i.e., a high NMR) is associated with lower cigarette smoking abstinence rates using transdermal nicotine replacement. We evaluated whether the NMR can be used to predict self-reported nicotine lozenge use and tobacco abstinence among smokeless tobacco users treated for tobacco dependence. This was a secondary analysis of data from one arm of a large trial. Participants received quitting support materials and 4-mg nicotine lozenges by mail plus three coaching phone calls. Saliva kits were mailed for collection of saliva samples, which were analyzed for cotinine and 3'-hydroxycotinine. Self-reported tobacco and lozenge use were assessed at 3 months. Analyses were performed using Spearman rank correlation and logistic regression. Of the 160 saliva collection kits mailed, 152 were returned. The NMR was not significantly correlated with the baseline amount of smokeless tobacco used, the number of years of tobacco use, or the level of tobacco dependence as measured by the Severson Scale of Tobacco Dependence. The NMR was positively correlated with lozenge use (r = 0.21, p = .015), but it did not predict self-reported 7-day point prevalence abstinence at 3 months. Fast metabolizers may need to self-administer more nicotine replacement in the form of nicotine lozenges to achieve the same clinical response achieved by slower metabolizers using fewer lozenges. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    Nicotine & Tobacco Research 05/2015; DOI:10.1093/ntr/ntv102 · 2.81 Impact Factor
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    ABSTRACT: Background: Cardiovascular disease is the leading cause of death, and smoking cessation is a key component of secondary cardiovascular disease risk prevention efforts. Objectives: To examine the relationships between demographic, clinical and health factors, history and patterns of smoking, nicotine dependence, withdrawal symptoms, and willingness (i.e., readiness) to quit smoking after hospital discharge among adult Jordanian men who were cigarette smokers and were admitted to the hospital with a cardiovascular disease diagnosis. Methods: This cross-sectional study recruited 118 adult men smokers from three hospitals in Jordan during 2011. Data were collected using structured interviews and medical record abstraction. Results: The mean age of smokers was 50.7 (±6.7) years and they smoked at least one cigarette per day for an average of 28.8 years (±7.0). Currently they smoke an average of 28.9 (±8.0) cigarettes a day. About a quarter (24.6%, n = 29) had previously made a quit attempt that lasted at least 24 hours. Smokers were considered highly nicotine dependent if they had scores of > 6 (out of 10) on the Fagerström Test for Nicotine Dependence scale. The average nicotine dependence score was significantly higher in the high versus low nicotine dependence group (6.9 vs. 4.1). The number of cigarettes smoked daily was significantly higher in the high compared to the low nicotine dependence group (30.7 cigarettes vs. 23.4). Logistic regression showed smokers who had someone available to encourage quitting smoking “at least sometimes” were more likely to quit smoking after hospital discharge, and smokers who had sufficient personal income to support self were less likely to quit smoking after hospital discharge, while controlling for all other variables. Conclusions: The very high nicotine dependence of these men indicates that there is an urgent need for education, counseling and behavioral interventions, and pharmacological therapies, to achieve successful smoking cessation. Study findings lay the basis for development of appropriate smoking cessation programs in Jordan.
    05/2015; 5(5):21-34. DOI:10.5430/jnep.v5n5p21
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    ABSTRACT: Smokeless tobacco products, such as moist snuff or chewing tobacco, contain many of the same carcinogens as tobacco smoke; however the impact on children of indirect exposure to tobacco constituents via parental smokeless tobacco use is unknown. As part of the California Childhood Leukemia Study, dust samples were collected from 6 homes occupied by smokeless tobacco users, 6 homes occupied by active smokers, and 20 tobacco-free homes. To assess children's potential for exposure to tobacco constituents, vacuum-dust concentrations of five tobacco-specific nitrosamines, including N'-nitrosonornicotine [NNN] and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK], as well as six tobacco alkaloids, including nicotine and myosmine were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). We used generalized estimating equations derived from a multivariable marginal model to compare levels of tobacco constituents between groups, after adjusting for a history of parental smoking, income, home construction date, and mother's age and race/ethnicity. The ratio of myosmine:nicotine was used as a novel indicator of the source of tobacco contamination, distinguishing between smokeless tobacco products and tobacco smoke. Median dust concentrations of NNN and NNK were significantly greater in homes with smokeless tobacco users compared to tobacco-free homes. In multivariable models, concentrations of NNN and NNK were 4.8-fold and 6.9-fold higher in homes with smokeless tobacco users compared to tobacco-free homes. Median myosmine:nicotine ratios were lower in homes with smokeless tobacco users (1.8%) compared to homes of active smokers (7.7%), confirming that cigarette smoke was not the predominant source of tobacco constituents in homes with smokeless tobacco users. Children living with smokeless tobacco users may be exposed to carcinogenic tobacco-specific nitrosamines via contact with contaminated dust and household surfaces.
    Chemical Research in Toxicology 03/2015; 28(5). DOI:10.1021/acs.chemrestox.5b00040 · 4.19 Impact Factor
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    ABSTRACT: A number of candidate gene and genome-wide association studies have identified significant associations between single nucleotide polymorphisms, particularly in FTO and MC4R, and body weight. However, the association between copy number variation and body weight is less understood. Anabolic androgenic steroids, such as testosterone, can regulate body weight. In humans, UDP-glucuronosyltransferase 2B17 (UGT2B17) metabolizes testosterone to a metabolite, which is readily excreted in urine. We investigate the association between genetic and phenotypic variation in UGT2B17 and body weight. UGT2B17 deletion was genotyped and in-vivo UGT2B17 enzymatic activity (as measured by the 3-hydroxycotinine glucuronide to free 3-hydroxycotinine ratio) was measured in 400 Alaska Native individuals and 540 African Americans. In Alaska Native people, UGT2B17 deletion was strongly associated with lower BMI in male individuals (P<0.001), but not in female individuals, consistent with testosterone being a male dominant steroid. The sex-specific association between UGT2B17 deletion and lower BMI was also observed in African Americans (P=0.01 in male individuals). In both populations, UGT2B17 deletion was significantly associated with lower measured in-vivo UGT2B17 activity. In male individuals, lower in-vivo UGT2B17 activity was associated with lower BMI, as observed in the sex-specific genotypic association. These data suggest that UGT2B17 deletion leads to reduced UGT2B17 activity, and lower BMI in male individuals. This is consistent with the hypothesis that reduced UGT2B17-mediated testosterone excretion results in higher testosterone levels. Future studies could confirm this hypothesis by directly measuring serum testosterone levels.
    Pharmacogenetics and Genomics 03/2015; 25(5). DOI:10.1097/FPC.0000000000000135 · 3.45 Impact Factor
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    ABSTRACT: In recent years, new products have entered the marketplace that complicate decisions about tobacco control policies and prevention in the workplace. These products, called electronic cigarettes (e-cigarettes) or electronic nicotine delivery systems, most often deliver nicotine as an aerosol for inhalation, without combustion of tobacco. This new mode of nicotine delivery raises several questions about the safety of the product for the user, the effects of secondhand exposure, how the public use of these products should be handled within tobacco-free and smoke-free air policies, and how their use affects tobacco cessation programs, wellness incentives, and other initiatives to prevent and control tobacco use. In this article, we provide a background on e-cigarettes and then outline key policy recommendations for employers on how the use of these new devices should be managed within worksite tobacco prevention programs and control policies.
    Journal of occupational and environmental medicine / American College of Occupational and Environmental Medicine 03/2015; 57(3):334-43. DOI:10.1097/JOM.0000000000000420 · 1.80 Impact Factor
  • Rachel Grana, Neal Benowitz, Stanton Glantz
    Circulation 02/2015; 131(6):e342-e342. DOI:10.1161/CIRCULATIONAHA.114.012887 · 14.95 Impact Factor
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    ABSTRACT: Substantial variability exists in therapeutic response and adverse effects with pharmacotherapies for tobacco dependence. Biomarkers to optimise treatment choice for individual smokers might improve treatment outcomes. We tested whether a genetically informed biomarker of nicotine clearance, the nicotine metabolite ratio (NMR; 3'-hydroxycotinine:cotinine), predicts response to nicotine patch or varenicline for smoking cessation. We undertook NMR-stratified multicentre, randomised, placebo-controlled clinical trial from Nov 16, 2010, to Sept 12, 2014, at four sites. Smokers seeking treatment were randomly assigned by baseline NMR status and study site, in blocks of 12 patients (1:1:1 ratio), to 11 weeks of placebo (placebo pill plus placebo patch), nicotine patch (active patch plus placebo pill), or varenicline (active pill plus placebo patch), plus behavioural counselling. Participants and investigators were masked to group allocation and NMR status. An intention-to-treat analysis was done. Participants were followed up for 12 months after the target quit date. The primary endpoint was biochemically verified 7 day point prevalence abstinence at the end of treatment to estimate the pharmacological effect of treatment by NMR. The trial is registered at ClinicalTrials.gov, number NCT01314001. 1246 participants (662 slow metabolisers of nicotine, 584 normal metabolisers of nicotine) were enrolled and randomly assigned to the three interventions (408 placebo, 418 nicotine patch, 420 varenicline). At end of treatment, varenicline was more efficacious than nicotine patch in normal metabolisers (OR 2·17, 95% CI 1·38-3·42; p=0·001), but not in slow metabolisers (OR 1·13, 0·74-1·71; p=0·56). In the longitudinal model including all timepoints, the NMR-by-treatment interaction was significant (ratio of odds ratios [ORR] 1·96, 95% CI 1·11-3·46; p=0·02). An NMR-by-treatment interaction showed that slow (vs normal) metabolisers reported greater overall side-effect severity with varenicline versus placebo (β=-1·06, 95% CI -2·08 to -0·03; p=0·044). Treating normal metabolisers with varenicline and slow metabolisers with nicotine patch could optimise quit rates while minimising side-effects. National Institutes of Health, Canadian Institutes of Health Research, Abramson Cancer Center, Centre for Addiction and Mental Health Foundation, and Pennsylvania Department of Health. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Respiratory Medicine 01/2015; 3(2). DOI:10.1016/S2213-2600(14)70294-2
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    ABSTRACT: The Food and Drug Administration (FDA) has the authority to regulate tobacco product constituents, including nicotine, to promote public health. Reducing the nicotine content in cigarettes may lead to lower levels of addiction. Smokers however may compensate by smoking more cigarettes and/or smoking more intensely. The objective of this study was to test whether individual differences in the level of nicotine dependence (as measured by the Fagerstrom Test of Cigarette Dependence, FTCD) and/or the rate of nicotine metabolism influence smoking behavior and exposure to tobacco toxicants when smokers are switched to reduced nicotine content cigarettes (RNC). Data from 51 participants from a previously published clinical trial of RNC were analyzed. Nicotine content of cigarettes was progressively reduced over six months and measures of smoking behavior, as well as nicotine metabolites and tobacco smoke toxicant exposure, CYP2A6 and nicotinic CHRNA5-A3-B4 (rs1051730) genotype were measured. Higher baseline FTCD predicted smoking more cigarettes per day (CPD), higher cotinine and smoke toxicant levels while smoking RNC throughout the study, with no interaction by RNC level. Time to first cigarette (TFC) was associated with differences in compensation. TFC within 10 min was associated with a greater increase in CPD compared to TFC greater than 10 min. Neither rate of nicotine metabolism, nor CYP2A6 or nicotinic receptor genotype, had an effect on the outcome variables of interest. FTCD is associated with overall exposure to nicotine and other constituents of tobacco smoke, while a short TFC is associated with an increased compensatory response after switching to RNC. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    Nicotine & Tobacco Research 01/2015; DOI:10.1093/ntr/ntu337 · 2.81 Impact Factor
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    ABSTRACT: Differences in carcinogen exposure from different cigarette products could contribute to differences in smoking-associated cancer incidence among Chinese compared with US smokers. Urine concentrations of metabolites of nicotine, the tobacco-specific nitrosamine (TSNA) 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and polycyclic aromatic hydrocarbon metabolites (PAHs) were compared in 238 Chinese and 203 US daily smokers. Comparing Chinese versus US smokers, daily nicotine intake and nicotine intake per cigarette smoked were found to be similar. When normalised for cigarettes per day, urine NNAL excretion was fourfold higher in US smokers, while the excretion of urine metabolites of the PAHs fluorene, phenanthrene and pyrene metabolites was 50% to fourfold higher in Chinese smokers (all, p<0.0001). Similar results were seen when NNAL and PAHs excretion was normalised for daily nicotine intake. Patterns of carcinogen exposure differ, with lower exposure to TSNA and higher exposure to PAHs in Chinese compared with US smokers. These results most likely reflect country differences in cigarette tobacco blends and manufacturing processes, as well as different environmental exposures. NCT00264342. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Tobacco Control 12/2014; DOI:10.1136/tobaccocontrol-2014-051945 · 5.15 Impact Factor
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    ABSTRACT: Reducing the addictiveness of cigarettes by reducing their nicotine content can potentially have a profound impact on public health. Two different approaches to nicotine reduction have been proposed: gradual and immediate. To determine if either of these approaches results in significant compensatory smoking behavior, which might lead to safety concerns, we performed a secondary analysis of data from studies that have utilized these two approaches. The number of cigarettes smoked per day, carbon monoxide exposure, and cotinine levels in plasma or urine were assessed while participants smoked reduced nicotine content cigarettes and compared to when they smoked their usual brand cigarettes. The results showed that in general, these two approaches led to minimal compensatory smoking and reduced levels of cotinine over the course of the experimental period, suggesting that neither of these approaches poses a major safety concern. Copyright © 2014, American Association for Cancer Research.
    Cancer Epidemiology Biomarkers & Prevention 12/2014; 24(2). DOI:10.1158/1055-9965.EPI-14-0739 · 4.32 Impact Factor
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    ABSTRACT: Background: The reduction of the nicotine content of cigarettes to non-addicting levels is a potential federal regulatory intervention to reduce the prevalence of cigarette smoking and related disease. Many clinical trials on the effects and safety of nicotine reduction are ongoing. An important methodological concern is non-compliance with reduced nicotine content cigarettes in the context of freely available conventional cigarettes. We propose two approaches using biomarkers to estimate non-compliance in smokers of very low nicotine content (VLNC) cigarettes in a clinical trial. Methods: Data from 50 subjects in a study of gradual nicotine reduction were analyzed. Using plasma cotinine concentrations measured at baseline and while smoking VLNC cigarettes, we compared within-subject ratios of plasma cotinine comparing usual brand to VLNC in relation to nicotine content of these cigarettes. In another approach we used nicotine pharmacokinetic data to estimate absolute plasma cotinine/cigarettes per day (CPD) threshold values for compliance based on the nicotine content of VLNC. Results: The two approaches showed concordance indicating at least 60% non-compliance with smoking VLNC. In a sensitivity analysis assuming extreme compensation and extreme values for nicotine metabolic parameters, non-compliance was still at least 40%, much higher than self-reported non-compliance. Conclusion: Biomarker analysis demonstrates a high degree of non-compliance with smoking VLNC cigarettes, indicating that smokers are supplementing these with conventional cigarettes. Impact: We propose a practical approach to assessing compliance with smoking VLNC in clinical trials of nicotine reduction. Copyright © 2014, American Association for Cancer Research.
    Cancer Epidemiology Biomarkers & Prevention 11/2014; 24(2). DOI:10.1158/1055-9965.EPI-14-1040 · 4.32 Impact Factor
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    ABSTRACT: Volatile organic compounds (VOC) from tobacco smoke are associated with cancer, cardiovascular, and respiratory diseases. The objective of this study was to characterize the exposure of nonsmokers to VOCs from secondhand smoke (SHS) in vehicles using mercapturic acid metabolites.
    Cancer Epidemiology Biomarkers & Prevention 11/2014; 23(12). DOI:10.1158/1055-9965.EPI-14-0548 · 4.32 Impact Factor
  • JAMA Internal Medicine 11/2014; 175(1). DOI:10.1001/jamainternmed.2014.5476 · 13.25 Impact Factor
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    ABSTRACT: Context. 4-Fluoroamphetamine (4-FA) is a para-substituted phenethylamine-type synthetic stimulant that has in recent years gained popularity through internet blogs and market share according to confiscated drug data. No serious toxicity has previously been reported. We report a case of a young man who developed severe toxicity and cardiogenic shock after using 4-FA, with laboratory confirmation. Case details. An 18-year-old man presented to the emergency department with vomiting, shortness of breath, chest tightness, and altered mental status about 5 h after using a new and unfamiliar street drug. Two days prior, he had received naltrexone intramuscular injection as part of an opioid addiction treatment program and was taking fluoxetine and trazodone. Five hours after presentation, he developed cardiogenic shock requiring intraaortic balloon pump, inotropic and ventilatory support. An echocardiogram showed left ventricular (LV) hypokinesia, sparing the apex and ejection fraction (EF) = 10%. Comprehensive toxicology serum testing revealed FA, naproxen, trazodone, and cotinine. The 4-FA urine level was 64,000 ng/ml and serum level was 118 ng/ml. With slow recovery, the patient was discharged after 2 weeks of hospitalization. Discussion. Although no previously reported 4-FA clinical poisoning cases have been published for comparison, by examining 4-FA pharmacology compared with other stimulant drugs, and given this patient's presentation and echocardiogram suggestive of reverse takotsubo cardiomyopathy we suspect the toxic mechanism was an acute cardiomyopathy caused by 4-FA catecholamine-induced myocarditis and/or small vessel myocardial ischemia. Conclusion. Recreational use of 4-FA may present with life threatening toxicity including cardiomyopathy, cardiogenic shock, and pulmonary edema.
    Clinical Toxicology 10/2014; 52(10). DOI:10.3109/15563650.2014.974262 · 3.12 Impact Factor
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    ABSTRACT: Background: Identifying sources of variation in the nicotine and nitrosamine metabolic inactivation pathways is important to understanding the relationship between smoking and cancer risk. Numerous UGT1A and UGT2B enzymes are implicated in nicotine and nitrosamine metabolism in vitro; however, little is known about their roles in vivo. Methods: Within UGT1A1, UGT1A4, UGT1A9, UGT2B7, UGT2B10, and UGT2B17, 47 variants were genotyped, including UGT2B10*2 and UGT2B17*2. The association between variation in these UGTs and glucuronidation activity within European and African American current smokers (n=128), quantified as urinary ratios of the glucuronide over unconjugated compound for nicotine, cotinine, trans-3'-hydroxycotinine, and NNAL, was investigated in regression models assuming a dominant effect of variant alleles. Results: Correcting for multiple testing, three UGT2B10 variants were associated with cotinine glucuronidation, rs2331559 and rs11726322 in European Americans and rs835309 in African Americans (P≤.0002). Additional variants predominantly in UGT2B10 were nominally associated with nicotine (P=.008-.04) and cotinine (P=<.001-.02) glucuronidation in both ethnicities in addition to UGT2B10*2 in European Americans (P=.01, P<.001). UGT2B17*2 (P=.03) in European Americans and UGT2B7 variants (P=.02-.04) in African Americans were nominally associated with 3HC glucuronidation. UGT1A (P=.007-.01), UGT2B10 (P=.02) and UGT2B7 (P=.02-03) variants in African Americans were nominally associated with NNAL glucuronidation. Conclusions: Findings from this initial in vivo study support a role for multiple UGTs in the glucuronidation of tobacco-related compounds in vivo, in particular UGT2B10 and cotinine glucuronidation. Impact: Findings also provide insight into ethnic differences in glucuronidation activity, which could be contributing to ethnic disparities in the risk for smoking-related cancers.
    Cancer Epidemiology Biomarkers & Prevention 10/2014; 24(1). DOI:10.1158/1055-9965.EPI-14-0804 · 4.32 Impact Factor
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    ABSTRACT: Bupropion is used clinically to treat depression and to promote smoking cessation. It is metabolized by CYP2B6 to its active metabolite hydroxybupropion, yet alterations in CYP2B6 activity have little impact on bupropion plasma levels. Furthermore, less than 10% of a bupropion dose is excreted as urinary bupropion and its characterized metabolites hydroxybupropion, threohydrobupropion and erythrohydrobupropion, suggesting that alternative metabolic pathways may exist. In vitro data suggested CYP2C19 could metabolize bupropion. The current study investigated the impact of functional CYP2C19 genetic variants on bupropion pharmacokinetics and treatment outcomes. In 42 healthy volunteers, CYP2C19*2 (a reduced activity allele) was associated with higher bupropion AUC, but similar hydroxybupropion AUC. The mean bupropion AUC was 771 versus 670h.ng/mL in individuals with, and without, CYP2C19*2 respectively (P=0.017). CYP2C19*2 was also associated with higher threohydrobupropion and erythrohydrobupropion AUC (P<0.005). Adjusting for CYP2B6 genotype did not alter these associations, and CYP2C19 variants did not alter the utility of the hydroxybupropion/bupropion ratio as a measure of CYP2B6 activity. Finally, in a clinical trial of 540 smokers, CYP2C19 genotype was not associated with smoking cessation outcomes supporting the hypothesis that bupropion response is mediated by hydroxybupropion, which is not altered by CYP2C19. In conclusion, our study reports the first in vivo evidence that reduced CYP2C19 activity significantly increases the steady state exposure to bupropion and its reductive metabolites threohydrobupropion and erythrohydrobupropion. These pharmacokinetic changes were not associated with differences in bupropion's ability to promote smoking cessation in smokers, but may influence the side effects and toxicity associated with bupropion.
    Drug metabolism and disposition: the biological fate of chemicals 09/2014; DOI:10.1124/dmd.114.060285 · 3.33 Impact Factor
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    Circulation 08/2014; 130(16). DOI:10.1161/CIR.0000000000000107 · 14.95 Impact Factor

Publication Stats

26k Citations
4,271.02 Total Impact Points

Institutions

  • 1979–2015
    • San Francisco VA Medical Center
      San Francisco, California, United States
    • Clinical pharmacology of Miami
      Miami, Florida, United States
  • 1976–2015
    • University of California, San Francisco
      • • Department of Bioengineering and Therapeutic Sciences
      • • Division of Clinical Pharmacology & Experimental Therapeutics
      • • Department of Clinical Pharmacy
      • • Department of Medicine
      • • Department of Physiological Nursing
      • • Department of Oral and Maxillofacial Surgery
      • • Division of Hospital Medicine
      • • Department of Psychiatry
      San Francisco, California, United States
  • 1999–2014
    • Stanford University
      • • Department of Medicine
      • • Stanford Prevention Research Center
      Palo Alto, California, United States
  • 2012
    • University of Minnesota Twin Cities
      • Department of Family Medicine and Community Health
      Minneapolis, MN, United States
    • Emory University
      • Department of Behavioral Sciences and Health Education
      Atlanta, Georgia, United States
  • 2010
    • University of Oulu
      • Department of Internal Medicine
      Uleoborg, Oulu, Finland
  • 2007–2010
    • University of Toronto
      • Department of Pharmacology and Toxicology
      Toronto, Ontario, Canada
    • Robert Wood Johnson University Hospital
      New Brunswick, New Jersey, United States
  • 2009
    • Jazz Pharmaceuticals plc
      Dublin, Leinster, Ireland
  • 2007–2009
    • San Diego State University
      • • Graduate School of Public Health
      • • Department of Psychology
      San Diego, CA, United States
  • 2008
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
  • 1995–2008
    • CSU Mentor
      Long Beach, California, United States
  • 1990–2007
    • University of Pittsburgh
      • Psychology
      Pittsburgh, Pennsylvania, United States
  • 2006
    • Johns Hopkins University
      • Department of Biostatistics
      Baltimore, MD, United States
    • Environmental Science & Research
      Окленд, Auckland, New Zealand
    • IWK Health Centre
      Halifax, Nova Scotia, Canada
    • Columbia University
      • Department of Psychiatry
      New York City, NY, United States
  • 2004–2006
    • University of Pennsylvania
      • Department of Psychiatry
      Philadelphia, PA, United States
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem, Israel
    • Boston College, USA
      Boston, Massachusetts, United States
  • 2005
    • University of Michigan
      Ann Arbor, Michigan, United States
    • Instituto Nacional de Salud Pública
      Cuernavaca, Morelos, Mexico
  • 1998–2002
    • University of San Francisco
      San Francisco, California, United States
    • American Society for Pharmacology and Experimental Therapeutics
      Maryland, United States
  • 2000
    • Skidmore College
      Saratoga Springs, New York, United States
  • 1994–1998
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
  • 1997
    • Baylor College of Medicine
      • Section of Cardiology
      Houston, Texas, United States
  • 1993
    • San Francisco Bay Area for Cognitive Therapy
      San Francisco, California, United States
  • 1992
    • Eli Lilly
      Indianapolis, Indiana, United States
  • 1991
    • National Cancer Institute (USA)
      • Occupational and Environmental Epidemiology
      Maryland, United States
  • 1989
    • The University of Arizona
      • College of Pharmacy
      Tucson, AZ, United States
  • 1988
    • Oregon Health and Science University
      • Department of Pediatrics
      Portland, OR, United States
  • 1984
    • Case Western Reserve University
      Cleveland, Ohio, United States