DNA and hemoglobin alkylation by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in F344 rats.
Alkylation of DNA and hemoglobin was compared in male F344 rats given a single s.c. injection of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), or its major metabolite formed by carbonyl reduction, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). In hepatic DNA, levels of 7-methylguanine and O6-methylguanine formed from NNK 1-48 h after treatment were similar to those formed from NNAL. In nasal mucosa and lung DNA, levels of 7-methylguanine and O6-methylguanine were somewhat higher after treatment with NNK than with NNAL. Acid hydrolysis of hepatic DNA, isolated from rats treated with either [5-3H]NNK or [5-3H]NNAL, gave 180 +/- 48 or 120 +/- 23 mumol/mol guanine, respectively, of 4-hydroxy-1-(3-pyridyl)-1-butanone. Basic hydrolysis of globin isolated from rats treated with either [5-3H]NNK or [5-3H]NNAL gave 4.1 +/- 0.7 or 2.0 +/- 0.1 pmol/mg, respectively of 4-hydroxy-1-(3-pyridyl)-1-butanone. These results indicate that NNAL is not a detoxification product of NNK, since treatment of rats with NNAL results in modifications of DNA which are qualitatively and quantitatively similar to those observed upon treatment with NNK. Alkylation of DNA and globin by NNAL may result mainly from its metabolic reconversion to NNK.
Hecht
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American Health Foundation, Valhalla, NY 10595.
Trushin
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D000477:Alkylating Agents; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D006147:Guanine / Q000031:analogs & derivatives; D006454:Hemoglobins; D006900:Hydroxylation; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D009297:Nasal Mucosa / Q000378:metabolism; D009602:Nitrosamines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D000477:Alkylating Agents; D006454:Hemoglobins; D009602:Nitrosamines; D006147:Guanine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D004247:DNA