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Formation of Hemoglobin Adducts upon Treatment of F344 Rats with the Tobacco-specific Nitrosamines 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone and N'-Nitrosonornicotine¹

Division of Chemical Carcinogenesis, Naylor Dana Institute for Disease Prevention of the American Health Foundation, Valhalla, New York 10595

[5-³H]4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone ([5-³H]NNK), [C³H₃]NNK, and [5-³H]N'-nitrosonornicotine ([5-³H]NNN) were administered to F344 rats by i.p. injection. Levels of tritium present per milligram globin, 24 h after treatment were 720 fmol (0.1% of dose) for [5-³H]NNK, 640 fmol for [C³H₃]NNK, and 370 fmol for [5-³H]NNN. Tritium was detectable in globin 7–8 weeks after treatment with [5-³H]NNK or [5-³H]NNN. Approximately 10–15% of the bound tritium in the globin of rats treated with [5-³H]NNK was released upon incubation of the globin with dilute NaOH or HCl. The released material was identified as 4-hydroxy-1-(3-pyridyl)-1-butanone; it was detectable in globin for 6 weeks (t = 9.1 days) after administration of [5-³H]NNK. 4-Hydroxy-1-(3-pyridyl)-1-butanone was also formed upon NaOH treatment of globin isolated from rats injected with [5-³H]NNN or [5-³H]4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone. The formation of 4-hydroxy-1-(3-pyridyl)-1-butanone under these conditions is consistent with a mechanism by which 4-(3-pyridyl)-4-oxobutyldiazohydroxide is produced upon metabolic -hydroxylation of NNK or NNN and binds to globin of hemoglobin, yielding an adduct which is readily hydrolyzed by acid or base. Support for this mechanism was obtained by in vitro experiments. Levels of 4-hydroxy-1-(3-pyridyl)-1-butanone released upon base treatment of globin were 50 times greater after incubation of rat hemoglobin with [5-³H]4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone than with either [5-³H]NNK or [5-³H]4-hydroxy-1-(3-pyridyl)-1-butanone. The results of this study suggest methods that might be applicable for assessing the molecular dosimetry of NNK and NNN in individuals exposed to tobacco and tobacco smoke.

¹ This study was supported by Research Grant P01-CA-29580 from the National Cancer Institute. This is paper 101 in "A Study of Chemical Carcinogenesis."

² To whom requests for reprints should be addressed, at Division of Chemical Carcinogenesis, Naylor Dana Institute for Disease Prevention, American Health Foundation, Dana Road, Valhalla, NY 10595.

Received 11/14/86. Revised 2/ 9/87. Accepted 2/13/87.

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