Perinatal Metabolism of the Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone in C57BL Mice23

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Abstract
Whole-body autoradiography of pregnant C57BL mice given iv injections of carbonyl-14C-labeled 4-(methylnitro-samino)-1-(3-pyridyl)-1-butanone (NNK) revealed that some metabolites were covalently bound to cellular macromolecules of the nasal mucosae, bronchial mucosae, and liver of the mother. Unbound metabolites were present in those tissues and were also localized in the gastrointestinal lumens, kidneys, urinary bladder, eye melanin, and corpora lutea of the ovaries. Autoradiograms taken at the 1-hour survival interval showed labeling of the fetal kidneys and urinary bladder. At the 4-hour survival interval, the amniotic fluid was strongly labeled. Chromatography of extracts of tissues obtained from pregnant mice on days 13 and 18 of gestation indicated that unchanged NNK and 4-(methylnitros-amino)-1-(3-pyridyl)butan-1-ol (NNAI) were present in the placentas and fetal tissues. Some NNK metabolites were covalently bound to tissues of the nose, lung, and liver of 18-day-old fetuses. These results indicate that NNK and NNAI have the capacity to cross the placental barrier and to be activated in fetal tissues. Nasal, pulmonary, and hepatic tissues of 16- and 18-day-old fetuses incubated in vitro with NNK metabolized NNK and NNAI by α-carbon hydroxylation. These pathways lead to intermediates able to alkylate cellular macromolecules. The nasal tissues had a higher capacity to α-carbon hydroxylate NNK than did pulmonary or hepatic tissues during the last stage of fetal development and during all stages of postnatal life. These results suggest that exposure of C57BL mice to NNK during the last stage of fetal development or during neonatal life could possibly result in development of tumors.