Cotinine effects on bile flow and biliary NNK elimination.
Nicotine and its major metabolite cotinine inhibit alpha-hydroxylation of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) suggesting that an alternative pathway of NNK metabolism and elimination, biliary excretion of the O-glucuronide of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL-Gluc) may be enhanced. To verify the possible role of cotinine on biliary elimination of NNK and its metabolites, bile duct cannulated rats were administered a single i.p. dose of 50 mg/kg [56sup;-3 H]-NNK with or without i.p. co-administration of 5 mg/kg cotinine or nicotine. Cotinine significantly reduced cumulative bile flow and biliary elimination of NNK-derived radioactivity within six hours to 42 and 27 percent, respectively. The pattern of NNK metabolites in bile was unchanged. Nicotine had a similar inhibitory effect on bile flow. This result constitutes the first experimental evidence that cotinine inhibits bile flow. In rats, biliary elimination of NNK is reduced accordingly which may lead to an increased carcinogen burden in the body. In humans, inhibition of bile flow by tobacco alkaloids may contribute to the appetite suppressing effect of tobacco products.
Meiser
H
H
Walther Straub Institute of Pharmacology and Toxicology, Nussbaumstr. 26, D-80336 Munich, Germany.
Atawodi
S E
SE
Richter
E
E
D000818:Animals; D001652:Bile Ducts / Q000378:metabolism*; D002273:Carcinogens / Q000008:administration & dosage / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D007274:Injections, Intraperitoneal; D008297:Male; D009538:Nicotine / Q000008:administration & dosage / Q000378:metabolism; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000378:metabolism; D009602:Nitrosamines / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D018722:Nicotinic Agonists; D009602:Nitrosamines; D009538:Nicotine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone