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Impact of Genetic Variants in the Nicotine Metabolism Pathway on Nicotine Metabolite Levels in Smokers
BACKGROUND: Nicotine metabolism is a major factor in nicotine dependence, with approximately 70% to 80% of nicotine metabolized to cotinine in Caucasians. Cotinine formation is catalyzed primarily by CYP2A6, which also converts cotinine to trans-3′-hydroxycotinine (3HC). The goal of the present stud...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Association for Cancer Research
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9827107/ https://www.ncbi.nlm.nih.gov/pubmed/36252563 http://dx.doi.org/10.1158/1055-9965.EPI-22-0868 |
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author | Perez-Paramo, Yadira X. Watson, Christy J.W. Chen, Gang Thomas, Claire E. Adams-Haduch, Jennifer Wang, Renwei Khor, Chiea Chuen Koh, Woon-Puay Nelson, Heather H. Yuan, Jian-Min Lazarus, Philip |
author_facet | Perez-Paramo, Yadira X. Watson, Christy J.W. Chen, Gang Thomas, Claire E. Adams-Haduch, Jennifer Wang, Renwei Khor, Chiea Chuen Koh, Woon-Puay Nelson, Heather H. Yuan, Jian-Min Lazarus, Philip |
author_sort | Perez-Paramo, Yadira X. |
collection | PubMed |
description | BACKGROUND: Nicotine metabolism is a major factor in nicotine dependence, with approximately 70% to 80% of nicotine metabolized to cotinine in Caucasians. Cotinine formation is catalyzed primarily by CYP2A6, which also converts cotinine to trans-3′-hydroxycotinine (3HC). The goal of the present study was to examine the effects of CYP2A6 deficiency on nicotine metabolism profiles in vivo and the importance of genetic variants in nicotine-metabolizing enzyme genes on urinary nicotine metabolites levels. METHODS: Urine samples from 722 smokers who participated in the Singapore Chinese Health Study were analyzed using UPLC-MS/MS to detect nicotine and eight of its urinary metabolites, and a total of 58 variants in 12 genes involved in nicotine metabolism were investigated in 475 of these subjects with informative genotyping data. RESULTS: Urine samples stratified by the ratio of 3HC/cotinine exhibited a 7-fold increase in nicotine-N’-oxide, a 6-fold increase in nicotine-Glucuronide (Gluc), and a 5-fold decrease in 3HC-Gluc when comparing the lower versus upper 3HC/cotinine ventiles. Significant (P < 0.0001) associations were observed between functional metabolizing enzyme genotypes and levels of various urinary nicotine metabolites, including CYP2A6 genotype and levels of nicotine, nicotine-Gluc, nicotine-N’-oxide and 3HC, UGT2B10 genotype and levels of cotinine, nicotine-Gluc and cotinine-Gluc, UGT2B17 genotype and levels of 3HC-Gluc, FMO3 genotype and levels of nicotine-N’-oxide, and CYP2B6 genotype and levels of nicotine-N’-oxide and 4-hydroxy-4-(3-pyridyl)-butanoic acid. CONCLUSIONS: These data suggest that several pathways are important in nicotine metabolism. IMPACT: Genotype differences in several nicotine-metabolizing enzyme pathways may potentially lead to differences in nicotine dependence and smoking behavior and cessation. |
format | Online Article Text |
id | pubmed-9827107 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-98271072023-01-10 Impact of Genetic Variants in the Nicotine Metabolism Pathway on Nicotine Metabolite Levels in Smokers Perez-Paramo, Yadira X. Watson, Christy J.W. Chen, Gang Thomas, Claire E. Adams-Haduch, Jennifer Wang, Renwei Khor, Chiea Chuen Koh, Woon-Puay Nelson, Heather H. Yuan, Jian-Min Lazarus, Philip Cancer Epidemiol Biomarkers Prev Research Articles BACKGROUND: Nicotine metabolism is a major factor in nicotine dependence, with approximately 70% to 80% of nicotine metabolized to cotinine in Caucasians. Cotinine formation is catalyzed primarily by CYP2A6, which also converts cotinine to trans-3′-hydroxycotinine (3HC). The goal of the present study was to examine the effects of CYP2A6 deficiency on nicotine metabolism profiles in vivo and the importance of genetic variants in nicotine-metabolizing enzyme genes on urinary nicotine metabolites levels. METHODS: Urine samples from 722 smokers who participated in the Singapore Chinese Health Study were analyzed using UPLC-MS/MS to detect nicotine and eight of its urinary metabolites, and a total of 58 variants in 12 genes involved in nicotine metabolism were investigated in 475 of these subjects with informative genotyping data. RESULTS: Urine samples stratified by the ratio of 3HC/cotinine exhibited a 7-fold increase in nicotine-N’-oxide, a 6-fold increase in nicotine-Glucuronide (Gluc), and a 5-fold decrease in 3HC-Gluc when comparing the lower versus upper 3HC/cotinine ventiles. Significant (P < 0.0001) associations were observed between functional metabolizing enzyme genotypes and levels of various urinary nicotine metabolites, including CYP2A6 genotype and levels of nicotine, nicotine-Gluc, nicotine-N’-oxide and 3HC, UGT2B10 genotype and levels of cotinine, nicotine-Gluc and cotinine-Gluc, UGT2B17 genotype and levels of 3HC-Gluc, FMO3 genotype and levels of nicotine-N’-oxide, and CYP2B6 genotype and levels of nicotine-N’-oxide and 4-hydroxy-4-(3-pyridyl)-butanoic acid. CONCLUSIONS: These data suggest that several pathways are important in nicotine metabolism. IMPACT: Genotype differences in several nicotine-metabolizing enzyme pathways may potentially lead to differences in nicotine dependence and smoking behavior and cessation. American Association for Cancer Research 2023-01-09 2022-10-17 /pmc/articles/PMC9827107/ /pubmed/36252563 http://dx.doi.org/10.1158/1055-9965.EPI-22-0868 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Research Articles Perez-Paramo, Yadira X. Watson, Christy J.W. Chen, Gang Thomas, Claire E. Adams-Haduch, Jennifer Wang, Renwei Khor, Chiea Chuen Koh, Woon-Puay Nelson, Heather H. Yuan, Jian-Min Lazarus, Philip Impact of Genetic Variants in the Nicotine Metabolism Pathway on Nicotine Metabolite Levels in Smokers |
title | Impact of Genetic Variants in the Nicotine Metabolism Pathway on Nicotine Metabolite Levels in Smokers |
title_full | Impact of Genetic Variants in the Nicotine Metabolism Pathway on Nicotine Metabolite Levels in Smokers |
title_fullStr | Impact of Genetic Variants in the Nicotine Metabolism Pathway on Nicotine Metabolite Levels in Smokers |
title_full_unstemmed | Impact of Genetic Variants in the Nicotine Metabolism Pathway on Nicotine Metabolite Levels in Smokers |
title_short | Impact of Genetic Variants in the Nicotine Metabolism Pathway on Nicotine Metabolite Levels in Smokers |
title_sort | impact of genetic variants in the nicotine metabolism pathway on nicotine metabolite levels in smokers |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9827107/ https://www.ncbi.nlm.nih.gov/pubmed/36252563 http://dx.doi.org/10.1158/1055-9965.EPI-22-0868 |
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