Dissertation
IMPACT OF GENOTYPE AND TOBACCO ADDITIVES ON CLEARANCE OF NNAL, AN IMPORTANT TOBACCO CARCINOGEN
Doctor of Philosophy (PhD), Washington State University
01/2019
Handle:
https://hdl.handle.net/2376/117139
Abstract
Tobacco remains the leading cause of preventable, premature death in adults world-wide. Among the most potent carcinogens in tobacco are the tobacco-specific nitrosamines, with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) the most potent as well as one of the most abundant. In vivo NNK is extensively metabolized to the equally carcinogenic 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). Of the two NNAL enantiomers, (S)-NNAL appears to be more carcinogenic than its (R)- counterpart within rodent models. Menthol, which creates mint flavor and scent, is often added to tobacco in both menthol and non-menthol cigarettes and has been shown to decrease the detoxification of NNAL. Due to the differential carcinogenic potential of the NNAL enantiomers, it is increasingly important to identify UGT enzyme targets the specific NNAL enantiomers for glucuronidation, to understand the UGTs involved in tissue-specific NNAL detoxification, and to characterize the mechanism of menthols inhibition of the NNAL detoxification pathway. To examine these, each of the six UGTs (1A4, 1A9, 1A10, 2B7, 2B10, 2B17) known to detoxify racemic NNAL were tested against pure NNAL enantiomers, targeted upper aerodigestive tissues were examined for stereo-selective NNAL-Gluc formation with racemic NNAL as a substrate, and urinary metabolites of NNAL and menthol were analyzed. In a screening of cells expressing individual UGT enzymes, all NNAL glucuronidating UGTs exhibited some level of stereo-specific preference for individual NNAL enantiomers, with UGTs 1A10 and 2B17 forming primarily (R)-NNAL-O-Gluc. Kinetic analysis indicated that 2B17 exhibited at least a 9-fold lower KM than UGT1A10. All tissue types preferentially formed (R)-NNAL-O-Gluc in the presence of racemic-NNAL; only esophagus exhibited any detectable formation of (S)-NNAL-O-Gluc. Levels of urinary NNAL-N-Gluc significantly (p<0.05) decreased among subjects with high levels of total urinary menthol, indicating that the presence of menthol could lead to NNAL being retained in the body longer, which could increase the opportunity for NNAL to damage DNA and lead to the development of tobacco-related cancers. These data demonstrate that variations in the expression or activity of specific UGTs may affect the clearance of specific NNAL enantiomers known to induce tobacco-related cancers.
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Details
- Title
- IMPACT OF GENOTYPE AND TOBACCO ADDITIVES ON CLEARANCE OF NNAL, AN IMPORTANT TOBACCO CARCINOGEN
- Creators
- Shannon Kozlovich
- Contributors
- Philip Lazarus (Advisor)Gang Chen (Committee Member)Michael Court (Committee Member)Shobhan Gaddameedhi (Committee Member)Kathryn Meier (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- College of Pharmacy and Pharmaceutical Sciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 178
- Identifiers
- 99900581706001842
- Language
- English
- Resource Type
- Dissertation