Effect of nicotine, cotinine and phenethyl isothiocyanate on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in the Syrian golden hamster

Toxicology. 2002 Sep 30;179(1-2):95-103. doi: 10.1016/s0300-483x(02)00321-9.


The effect of nicotine, cotinine and phenethyl isothiocyanate (PEITC) on metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was studied in the Syrian golden hamster. Urinary metabolite profiles were determined in 24 h urine after a single subcutaneous (s.c.) administration of [5-(3)H]NNK (80 nmol/kg, s.c.). Co-administration of either a 500-fold higher dose of nicotine (40 micromol/kg, s.c.) or a 5000-fold higher dose of cotinine (400 micromol/kg, s.c.) significantly (P<0.001) reduced metabolic activation of NNK by alpha-hydroxylation to 85 and 71% of control, respectively. Co-administration of a 300-fold higher dose of PEITC (1 micromol/g diet) slightly reduced alpha-hydroxylation of NNK (94% of control). Metabolism of NNK by reduction to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was increased by nicotine (155%), and significantly increased by cotinine (670%, P<0.001) and PEITC (219%, P<0.01). Detoxification of NNAL by glucuronidation was also increased by all three test agents. Detoxification of NNK and NNAL by N-oxidation was marginally increased by nicotine, reduced by PEITC, and significantly reduced by cotinine. The urinary metabolite profiles suggest that nicotine, which occurs in concentrations up to 30000-fold higher than NNK in mainstream cigarette smoke, and cotinine, its proximal metabolite, may have a significant protective effect against in vivo metabolic activation of NNK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biotransformation / drug effects
  • Cotinine / pharmacology*
  • Cricetinae
  • DNA Damage / drug effects
  • Female
  • Glucuronides / metabolism
  • Isothiocyanates / pharmacology*
  • Mesocricetus
  • Nicotine / pharmacology*
  • Nicotinic Agonists / pharmacology*
  • Nitrosamines / antagonists & inhibitors
  • Nitrosamines / metabolism*
  • Nitrosamines / urine
  • Tobacco / chemistry


  • Glucuronides
  • Isothiocyanates
  • Nicotinic Agonists
  • Nitrosamines
  • Nicotine
  • phenethyl isothiocyanate
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
  • Cotinine