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Molecular Dosimetry of DNA Adduct Formation and Cell Toxicity in Rat Nasal Mucosa following Exposure to the Tobacco Specific Nitrosamine 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone and Their Relationship to Induction of Neoplasia

Laboratory of Biochemical Risk Analysis [S. A. B., M. W. A.] and Chemical Pathology Branch [R. R. M.], National Institute of Environmental Health Sciences; and Department of Biochemical Toxicology and Pathobiology, Chemical Industry Institute of Toxicology [V. E. W., J. A. S.]; Research Triangle Park, North Carolina 27709

The molecular dosimetry of O⁶-methylguanine (O⁶MG) formation in DNA and cytotoxicity in respiratory and olfactory mucosa was determined during administration of 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to male Fischer 344 rats. The dose response for O⁶MG formation differed considerably between respiratory and olfactory mucosa. The dose response was nonlinear in respiratory mucosa where the slope of the curve was very large for doses of NNK ranging from 0.3 to 3.0 mg/kg but much smaller in the dose range of 10 to 100 mg/kg. In contrast, the dose response in the olfactory mucosa did not demonstrate such a large change in slope over the same dose range. The concentration of O⁶MG formed to dose of NNK ratio, an index of efficiency of alkylation, increased dramatically only in the respiratory mucosa as the dose of NNK was decreased from 100 to 0.3 mg/kg. The concentration of O⁶MG was four times greater in respiratory than olfactory mucosa after treatment of rats with 1 mg/kg NNK. Alkylation in the two regions of the nose became similar as the dose of NNK was increased. In rats treated for up to 12 days with NNK (10 mg/kg/day), the concentration of O⁶MG was 60 to 90% greater in respiratory than olfactory mucosa throughout treatment. Regional differences in the amount of O⁶MG formed may stem from the presence of a low K_m pathway for biotransformation of NNK in the cells of the respiratory mucosa. This conclusion is supported by autoradiographic studies. Four h after treatment with 1 mg/kg [³H]NNK, silver grains were more heavily concentrated in respiratory than olfactory epithelium. Histopathological examination of the nasal passages revealed dose related, cell specific differences in toxicity following treatment of rats with 10, 30, or 100 mg/kg NNK for 12 days. No toxicity was observed in the nose when 1 mg/kg NNK was administered. Bowman's glands underlying the olfactory mucosa and Steno's glands were the most sensitive sites for toxicity, exhibiting necrosis after as little as 2 days of treatment with 10 mg/kg NNK. Damage to these glands progressed in a dose- and time-dependent manner. Respiratory epithelium exhibited only mild toxicity while basal cell metaplasia was evident in olfactory epithelium. Rats treated with NNK for 20 weeks (50 mg/kg, three times a week) had a 45% incidence of carcinomas in the olfactory region. These neoplasms appeared to arise from Bowman's glands. In contrast, there was only a 5% incidence of malignant neoplasia and a 29% incidence of benign neoplasia in the respiratory region. Taken together, these data suggest that the formation of promutagenic adducts and cell proliferation secondary to toxicity are required for the induction of malignant tumors by NNK within the nose.

¹ Recipient of a National Research Service Award (ES05292) from the National Institute of Environmental Health Sciences. To whom requests for reprints should be addressed, at Biochemical Risk Analysis, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709.

Received 4/13/87. Revised 7/27/87. Accepted 8/14/87.

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