Longitudinal Influence of Pregnancy on Nicotine Metabolic Pathways

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 ( = 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 ( = 0.12) and 1.11-fold ( < 0.001) higher at early and late pregnancy, respectively, compared with postpartum. Nicotine N-glucuronidation was 1.33-fold ( = 0.06) and 1.67-fold ( = 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 < 0.05) and correlated with nicotine C-oxidation (all < 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 ( = 0.07 and < 0.05, respectively) and correlated with a second UGT2B10 phenotype ratio (cotinine glucuronide/cotinine) (all < 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.

Why Do Intrauterine Exposure to Air Pollution and Cigarette Smoke Increase the Risk of Asthma?

“…In particular, MSE is the largest modifiable risk factor for the development of asthma. Although the harmful effect of smoking is well-known in the general public, smoking mothers find it difficult to quit due to nicotine addiction, even during pregnancy when nicotine metabolism is faster than non-pregnant status (Taghavi et al, 2018). A systematic review and meta-analysis in the Lancet showed that the top 3 countries with the highest smoking rate during pregnancy are Ireland (38.4%), Uruguay (29.7%), and Bulgaria (29.4%) (Lange et al, 2018).…”

Cigarette consumption and biomarkers of nicotine exposure during pregnancy and postpartum

“…Individuals who metabolize nicotine faster (who have higher CYP2A6 activity and NMR) smoke more to maintain similar levels of nicotine in the body compared to slower nicotine metabolizers (who have lower CYP2A6 activity and NMR) (22, 23, 25). The rate of nicotine metabolism is accelerated during pregnancy as evidenced by faster nicotine clearance (26) and a lower proportion of nicotine excreted unchanged (as a fraction of TNE) (27). Estrogen levels begin to rise after conception and are approximately five-fold and twenty-fold higher at early and late pregnancy, respectively, compared to pre-pregnancy levels (27).…”

Pregnant Smokers Receiving Opioid Agonist Therapy Have an Elevated Nicotine Metabolite Ratio: A Replication Study

“…The gestational age did not differ by group, which obviated controlling for this potential effect on NMR. 5 Most patients in the OAT group were being treated with methadone ( n = 27 or 79.4%; mean daily dosage = 91.0 mg [ SD = 62.6]) with the remainder receiving buprenorphine ( n = 7 or 20.6%; mean daily dosage = 14.3 mg [ SD = 3.2]). One participant reported a confirmed daily methadone dose of 360 mg; for the other 26 participants, the mean daily dose was 80.62 mg ( SD = 32.70).…”

“…Neither CPD nor PHQ-9 score was associated with NMR. Although changes in NMR have been observed across pregnancy, 5 we tested women at approximately the same gestational age.…”

“…3 This is due, in part, to the induction of the enzymes CYP2A6 and UGT2B10 and a higher rate of nicotine metabolism, which begins by 12 weeks of gestation and continues throughout pregnancy. 4 , 5 …”