Impact of Genetic Variants in the Nicotine Metabolism Pathway on Nicotine Metabolite Levels in Smokers. Other Scholarly Work

Perez-Paramo, Yadira X, Watson, Christy JW, Chen, Gang et al. (2023). Impact of Genetic Variants in the Nicotine Metabolism Pathway on Nicotine Metabolite Levels in Smokers. . CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, 32(1), 54-65. 10.1158/1055-9965.epi-22-0868

cited authors

  • Perez-Paramo, Yadira X; Watson, Christy JW; Chen, Gang; Thomas, Claire E; Adams-Haduch, Jennifer; Wang, Renwei; Khor, Chiea Chuen; Koh, Woon-Puay; Nelson, Heather H; Yuan, Jian-Min; Lazarus, Philip

authors

abstract

  • 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.

publication date

  • January 1, 2023

keywords

  • Chromatography, Liquid
  • Cotinine
  • Cytochrome P-450 CYP2A6
  • Genotype
  • Glucuronosyltransferase
  • Humans
  • Nicotine
  • Smokers
  • Tandem Mass Spectrometry
  • Tobacco Use Disorder

Digital Object Identifier (DOI)

Medium

  • Print

start page

  • 54

end page

  • 65

volume

  • 32

issue

  • 1