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Metabolism and DNA Damage Induced by 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone in Fetal Tissues of the Syrian Golden Hamster¹

Laboratory of Cancer Etiology and Chemoprevention, School of Pharmacy, Laval University, Quebec City, Canada G1K 7P4 [G. R., M. A. A-J., A. C.], and the Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37901 [H. M. S.]

The nicotine derived N-nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent respiratory tract carcinogen in adult Syrian golden hamsters. In this study, the metabolism and genotoxicity of NNK was investigated in fetal hamster trachea and lung tissues. Fetal lung and tracheal explants were cultured in vitro with [5-³H]NNK, and metabolites released into the culture medium were assayed by high-performance liquid chromatography-scintigraphy. Activation of NNK by -carbon hydroxylation and deactivation by pyridine N-oxidation increased from Day 12 to 15 of fetal development. In lung tissues, at Day 12 of fetal development, carbonyl reduction of NNK to 4-(methylnitrosamino)-1-(3-pyridyl)butan-1-ol was a major metabolic pathway. When adult and fetal lung explants were cultured in vitro with [methyl-³H] NNK, explant DNA was methylated at the O⁶- and N-7 guanine sites. When hamsters were injected i.p. with NNK (0–200 mg/kg) on Day 14 of gestation, chromosome aberrations were observed in epithelial cells established from lung and tracheal explant outgrowths. Most aberrations in lung and tracheal cells were of chromatid types. High frequency of chromatid exchange was observed in tracheal cells. After injection of NNK (200 mg/kg) to 14-day pregnant hamsters, NNK was detected in lung (0.39 ± 0.16 nmol/mg), placenta (0.72 ± 0.48 nmol/mg protein) and amniotic fluids (34.07 ± 7.62 nmol/ml). These results demonstrated that NNK can cross the placental barrier in pregnant hamsters and be activated to genotoxic intermediates in tracheal and lung tissues and suggest that NNK is a transplacental carcinogen in this species.

¹ This study was supported by National Cancer Institute Grant CA-42829. Animals were treated according to the guidelines adopted by the Canadian Council on Animal Care.

² To whom requests for reprints should be addressed.

Received 2/16/89. Revised 6/27/89. Accepted 7/ 6/89.

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