Effect of nicotine, cotinine and phenethyl isothiocyanate on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in the Syrian golden hamster.
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.
Richter
Elmar
E
Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians University of Munich, Nussbaumstrasse 26, D-80336, Munich, Germany. franky.richter@lrz.uni-muenchen.de
Tricker
Anthony R
AR
D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D003367:Cotinine / Q000494:pharmacology*; D006224:Cricetinae; D004249:DNA Damage / Q000187:drug effects; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D017879:Isothiocyanates / Q000494:pharmacology*; D008647:Mesocricetus; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009602:Nitrosamines / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000652:urine
D020719:Glucuronides; D017879:Isothiocyanates; D018722:Nicotinic Agonists; D009602:Nitrosamines; D009538:Nicotine; C058305:phenethyl isothiocyanate; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D003367:Cotinine