Metabolism of nicotine and 4-(methylnitrosamino)-l-(3-pyridyl)-lbutanone (NNK) in menthol and non-menthol cigarette smokers

Drug Metab Lett. 2012 Sep 1;6(3):198-206. doi: 10.2174/1872312811206030007.


Purpose: Menthol in cigarettes has been suggested to inhibit metabolism of nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The objective of this study was to investigate the glucuronide metabolite ratios (MR) for nicotine (NICGLUC/NIC), cotinine (COTGLUC/COT), trans 3'-hydroxy cotinine (3OHCOTGLUC/3OHCOT). 4-methylnitrosamino-1-(3-pyridyl)-1-butanol (NNAL - NNALGLUC/NNAL); and the ratio of trans 3'-hydroxy cotinine tocotinine (3OHCOT/COT) between adult menthol and non-menthol smokers (AS).

Methods: The data was collected from the Total Exposure Study (TES), a stratified, multi-center, cross-sectional study that included 3,585 AS and 1,077 non-smokers. Daily urinary excretion of nicotine and five metabolites, NNAL and NNAL glucuronides, and serum cotinine were measured in the AS. The analysis included 1044 menthol (448 African-Americans, AA) and 2297 non-menthol (161 AA) AS.

Results: Smoking mentholated cigarettes did not decrease any of the MR. Race was the most important significant main effect for all the MRs. AAs exhibited statistically significantly lower NICGLUC/NIC, COTGLUC/COT, NNALGLUC/NNAL and 3OHCOT/COT, but higher 3OHCOTGLUC/3OHCOT compared to Whites. Age, liver function, alcoholic beverages, etc., were some of the other significant effects for some MRs. Menthol was not a statistically significant effect,e.g. the adjusted mean NNALGLUC/NNAL between menthol and non-menthol AS was 2.93 vs. 2.80 (p>0.05, AA) and3.38 vs. 3.35 (p>0.05, Whites). The models only explained 2.6-12.6% of the MR variability. Number of cigarettes was the most important factor affecting serum cotinine levels.

Conclusions: Menthol does not inhibit the metabolism of nicotine or NNK. The daily exposure of related constituents is primarily influenced by number of cigarettes smoked per day.

Publication types

  • Multicenter Study

MeSH terms

  • Adult
  • African Americans
  • Cotinine / blood
  • Cotinine / metabolism
  • Cross-Sectional Studies
  • European Continental Ancestry Group
  • Female
  • Glucuronides / urine
  • Humans
  • Male
  • Menthol / chemistry*
  • Middle Aged
  • Nicotine / metabolism*
  • Nicotine / urine
  • Nitrosamines / metabolism*
  • Nitrosamines / urine
  • Pyridines / metabolism
  • Pyridines / urine
  • Smoking / metabolism*
  • Tobacco Products
  • Young Adult


  • Glucuronides
  • Nitrosamines
  • Pyridines
  • Menthol
  • Nicotine
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
  • 4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol
  • Cotinine