Browsing by Subject "smoking"

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    Ethnic differences in the metabolism of 1,3-butadiene and lung cancer risk
    (2019-01) Boldry, Emily
    Cigarette smoking remains one of the most preventable causes of death in the world, and is the leading cause of lung cancer. Epidemiological studies show inherent differences in lung cancer risk among smokers of different ethnic groups, with Native Hawaiian and African Americans have the highest risk, European Americans having an intermediate risk, and Latinos and Japanese Americans having the lowest risk. It has been proposed that these disparities in risk are due to ethnic differences in the metabolism, and ultimately bioactivation, of carcinogens in present in cigarette smoke. 1,3-butadiene (BD) is one of the most abundant and potent carcinogens present in cigarette smoke. BD is metabolically activated to the reactive species 3,4-epoxy-1-butene (EB), hydroxymethylvinylketone (HMVK), 3,4-epoxy-1,2-butanediol (EBD), and 1,2,3,4-diepoxybutane (DEB), which have the ability to form pro-mutagenic DNA adducts. These species can be detoxified through glutathione conjugation and excreted in urine; EB and HMVK are excreted as 2-(N-acetyl-L-cystein-S-yl)-1-hydroxybut-3-ene/ 1-(N-acetyl-L-cystein-S-yl)-2-hydroxybut-3-ene (MHBMA) and 4-(N-acetyl-L-cystein-S-yl)-1,2-dihydroxybutane (DHBMA). The research presented in this thesis focuses on ethnic differences in BD metabolism and the initial development of a DEB specific biomarker. A high throughput HPLC-ESI--MS/MS method for the simultaneous quantitation of MHBMA and DHBMA in humans previously developed in our laboratory was applied to quantify these mercapturic acids in smokers of different ethnic groups. In a large multi-ethnic study composed of African American, European American, and Japanese American smokers (N = 1,072). Urinary MHBMA and MHBMA/MHBMA+DHBMA were highest in African Americans, followed by European Americans, and Japanese Americans, and strongly influenced by GSTT1 genotype. A genome wide association study (GWAS) revealed strong associations between MHBMA and GSTT1: associations with 136 SNPs were detected, and all of them were located between 24.2—24.4 Mb near the GSTT1 gene on chromosome 22q11. Additional experiments with recombinant human GSTT1 and GSTT2 confirmed EB as a substrate for the first time. The same method was also applied to a separate smaller study of African American and European American smokers (N = 151). In contrast to the previous work, urinary MHBMA was higher in European Americans than African Americans in this study; this is likely due to decreased sample size. Statistical analyses revealed no correlation between urinary MHBMA or DHBMA and urinary N7-(1-hydroxy-3-buten-2-yl)guanine (EBGII), as well no significant associations between urinary EBGII, MHBMA, or DHBMA and various specific SNPs from BD-metabolizing genes (EPHX1 and CYP2E1) and DNA repair genes (FANCE). GSTT1 copy number was also included in this analysis, and showed a significant association with urinary MHBMA. Urinary MHBMA and DHBMA were also quantified in smokers (N=79) receiving treatment with the chemopreventative agent 2-phenethyl isothiocyanate (PEITC). Overall, PEITC treatment resulted in only slight increases in MHBMA and DHBMA as compared to treatment with a placebo, but was found to significantly increase MHBMA in individuals null for GSTT1 or both GSTT1 and GSTM1, indicating a potential protective effect of PEITC in these individuals. Lastly, an HPLC-ESI+-MS/MS method for the of detection of a novel DEB-specific biomarker, Nε, Nε-(2,3-dihydroxybutan-1,4-diyl)-L-lysine (DHB-Lys) was explored. Initial development focused on the use of an ion-pairing agent, perfluoroheptanoic acid (PFHA), which was chosen to increase HPLC retention of DHB-Lys. Though addition of PFHA to the aqueous mobile phase during HPLC-ESI+-MS/MS analysis did result in increased retention of the analyte, its use also presented additional challenges with analyte carryover, sample contamination, and ion suppression. Methodology utilizing derivatization of DHB-Lys through the addition of a 6-aminoquinolyl group (6-AQ) at the alpha nitrogen was tested on DEB-treated O6-alkylguanine DNA alkyltransferase (AGT), and showed a dose dependent increase in DHB-Lys formed.
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    Examining the association between tobacco use and binge drinking and the effects of tobacco interventions on binge drinking behaviors
    (2012-03) Stahre, Mandy Adele
    Background: Binge drinking is a significant public health problem. Although effective alcohol control policies exist, many have eroded over time or face strong political opposition to their implementation. Other mechanisms to reduce binge drinking need to be found. Tobacco and alcohol use share similar biological, personal, and environmental characteristics and research has shown that among alcohol dependent population reducing smoking can lead to decreases in alcohol use. Objectives: The purpose of this dissertation was to assess: (1) the extent that binge drinking and smoking are associated in a non-alcohol dependent population, (2) how this observed association may be modified by individual- and environmental-level factors, and (3) the effect of tobacco interventions on binge drinking. Methods: The first study examined the association between binge drinking and smoking behaviors using a representative sample of active duty military personnel. Additionally, multivariate logistic regression tested whether frequency of deployment and the perception of an alcohol promoting environment moderated the association between binge drinking and smoking. The second study assessed the effect of an individual-level tobacco intervention (health education versus motivational interviewing counseling) on binge drinking and average daily alcohol use in a group of African American light smokers over a six-month period. Generalized linear models assessed the mediation effect of smoking cessation on the relationship between counseling intervention and drinking. The third study used pooled-time-series analyses to assess the effects of two state-level tobacco control policies (tobacco taxes and smoking bans in bars) on state-level binge drinking behaviors from 1998 to 2010. Results: In the first study, binge drinking was found to be significantly higher among current smokers than former and nonsmokers. The frequency of deployment (but not the perception of an alcohol-promoting environment) moderated this relationship although effects varied by branch of service. In the second study, individuals randomly assigned to receive health education counseling decreased their binge drinking at week 8 of the study, but these results diminished within six months. Smoking cessation did not appear to mediate the relationship between counseling type and binge drinking; however, individuals who quit smoking (regardless of counseling type) also decreased their binge drinking at week 8 of the study; these results were not significant at the end of the study. For the third study, neither tobacco taxes nor smoking bans in bars was associated with a decrease in binge drinking outcomes at the state level. Conclusions: Smoking and binge drinking are strongly associated in non-alcohol dependent populations and some evidence suggests that decreasing smoking leads to initial reductions in binge drinking; however, the evidence presented is not strong enough to advocate for a reliance on smoking interventions as a way to reduce and prevent binge drinking. Alcohol advocates need to continue to support and educate lawmakers about the effectiveness of alcohol control policies in order to reduce binge drinking.