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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2023
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.
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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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