Abstract
Nicotine metabolism increases in pregnancy, which may contribute to the difficulties that pregnant women have in quitting smoking. We aimed to determine the extent and timing of changes in nicotine metabolic pathways, including C-oxidation, N-glucuronidation, and the pregnancy-induced influences on the activity of enzymes mediating these pathways (CYP2A6 and UGT2B10, respectively). Current smoking pregnant women (n = 47) provided a urine sample during early pregnancy (12.5 weeks), late pregnancy (28.9 weeks), and 6 months postpartum. Concentrations of urinary nicotine and metabolites were analyzed using liquid chromatography tandem mass spectrometry and compared using general linear repeated measures analyses. Nicotine C-oxidation was 1.07-fold (P = 0.12) and 1.11-fold (P < 0.001) higher at early and late pregnancy, respectively, compared with postpartum. Nicotine N-glucuronidation was 1.33-fold (P = 0.06) and 1.67-fold (P = 0.003) higher at early and late pregnancy, respectively, compared with postpartum. The CYP2A6 phenotype ratio (total 3′-hydroxycotinine/cotinine) was significantly higher at early and late pregnancy compared with postpartum (all P < 0.05) and correlated with nicotine C-oxidation (all P < 0.001), suggesting CYP2A6 activity is induced during pregnancy. The UGT2B10 phenotype ratio (nicotine glucuronide/nicotine) was higher at early and late pregnancy compared with postpartum (P = 0.07 and P < 0.05, respectively) and correlated with a second UGT2B10 phenotype ratio (cotinine glucuronide/cotinine) (all P < 0.001), suggesting UGT2B10 activity is induced during pregnancy. In conclusion, pregnancy-induced increases in nicotine metabolism start by 12 weeks gestation and continue as pregnancy progresses most likely due to induction of CYP2A6 and UGT2B10, resulting in potential reductions in the effectiveness of nicotine replacement therapies and an increase in metabolism of other CYP2A6 and UGT2B10 substrates during pregnancy.
Footnotes
- Received September 13, 2017.
- Accepted November 15, 2017.
This work was supported in part by Canada Research Chairs program (R.F.T., Canada Research Chair in Pharmacogenomics). This work was also supported by Canadian Institutes of Health Research [Grant FDN-154294], Campbell Family Mental Health Research Institute of Centre for Addiction and Mental Health, Centre for Addiction and Mental Health Foundation, Canadian Foundation for Innovation [Grants 20289 and 16014 to R.F.T.], Ontario Ministry of Research and Innovation, National Institutes of Health National Institute on Drug Abuse [Grant R01DA014028], National Institutes of Health National Institute of Child Health and Human Development [Grant R01HD075669], Tobacco Centers of Regulatory Science [Grant P50DA036114], Food and Drug Administration, and National Institutes of Health National Institute of General Medical Sciences Center of Biomedical Research Excellence [Grant P20GM103644 to S.T.H.].
A preliminary account of this work was previously presented at the following meeting: Taghavi T, Arger CA, Heil SH, Higgins ST, and Tyndale RF (2017) Changes in nicotine metabolic pathways across pregnancy: a longitudinal study. 21st North American ISSX Meeting; 2017 September 24–28; Providence, RI.
Primary laboratory of origin: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics
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