The effect of tobacco smoke, nicotine, and cotinine on the mutagenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL).
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a rodent carcinogen that is metabolically derived from carbonyl reduction of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). NNAL can be pyridine N-oxidized to form NNAL-N-oxide, or conjugated to form NNAL-glucuronide - non-genotoxic metabolites that can be excreted in urine. Alternatively, NNAL can be alpha-hydroxylated at the methyl and methylene carbons adjacent to the nitroso group to generate electrophiles that can react with biological macromolecules, such as DNA and proteins. Our laboratory has previously demonstrated that the mutagenicity of NNK was significantly inhibited by the aqueous extract of tobacco smoke, as well as pyridine alkaloids in cigarette smoke, such as nicotine, cotinine and nornicotine. Given the structural similarity between NNK and NNAL, and the metabolic activation of both by cytochromes P450, we hypothesized that there may be a similar inhibition of NNAL metabolism, and consequently, inhibition of the mutagenic activity of NNAL by tobacco smoke and its pyridine alkaloid constituents. In the present study, we evaluated the ability of two pyridine alkaloids (nicotine and cotinine) and aqueous cigarette smoke condensate extract (ACTE) to inhibit the mutagenicity of NNAL in Salmonella typhimurium strain TA1535 in the presence of a metabolic activation system (S9). Both pyridine alkaloids tested, as well as ACTE, inhibited the mutagenicity of NNAL in a concentration-dependent manner. The observed reductions in mutagenicity were not the result of cell killing due to cytotoxicity. These results demonstrate that tobacco smoke contains pyridine alkaloids, as well as other unidentified constituents that inhibit the mutagenicity of NNAL, a major metabolite of NNK.
Brown
B
B
Environmental and Molecular Toxicology, Research and Development, P.O. Box 1236, R.J. Reynolds Tobacco Company, Winston-Salem, NC 27102, USA. brownbg@rjrt.com
Avalos
J
J
Lee
C
C
Doolittle
D
D
D002273:Carcinogens / Q000037:antagonists & inhibitors / Q000633:toxicity; D003367:Cotinine / Q000494:pharmacology*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity; D009538:Nicotine / Q000494:pharmacology*; D009602:Nitrosamines / Q000037:antagonists & inhibitors / Q000633:toxicity*; D012475:Salmonella / Q000187:drug effects; D012906:Smoke
D002273:Carcinogens; D009153:Mutagens; D009602:Nitrosamines; D012906:Smoke; D009538:Nicotine; C051577:4-(methylnitrosoamino)-4-(3-pyridyl)-1-butanol; D003367:Cotinine