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Placental Transfer of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Instilled Intratracheally in Syrian Golden Hamsters¹

Laboratory of Cancer Etiology and Chemoprevention, School of Pharmacy, Laval University, Québec City, Québec, Canada G1K 7P4 [R. J., A. C.], and Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37902-2071 [H. M. S.]

The tobacco-specific N-nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent tumorigen in adult Syrian golden hamsters and an active transplacental carcinogen in this species. In this study, we have investigated the biodistribution and metabolism of NNK in maternal and fetal hamster tissues as a function of the dose and the time after NNK treatment. Hamsters on day 15 of gestation were instilled intratracheally with single doses (0.05–100 mg/kg) of [5-³H]NNK and sacrificed 30 min later or treated with a single dose (25 mg/kg) of [5-³H] NNK and sacrificed at various times (5–360 min) after treatment. Total radioactivity was quantified in maternal tissues (liver, lung, kidney, placenta, and stomach), in whole fetus and in fetal tissues (liver and lung). NNK and its metabolites were extracted from selected tissues (maternal plasma, amniotic fluid, fetal liver, and lung) and assayed by high-performance liquid chromatography-scintigraphy. Thirty min after treatment, radioactivity associated with NNK and its metabolites showed similar widespread tissue distribution patterns at all doses, with a linear dose relationship observed in whole fetus and fetal tissues. NNK levels detected in maternal plasma, amniotic fluid, fetal liver, and lung were also related linearly to dose. At high doses (25 mg/kg or more) of NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol was the major metabolite detected in maternal plasma. Pyridine N-oxidation of NNK predominated at the lowest doses (0.05 and 0.5 mg NNK/kg). The toxicokinetics of NNK demonstrated that this carcinogen is rapidly absorbed from the maternal lung (<5 min), metabolized mainly to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and quickly distributed into the maternal-fetal compartment. Both NNK and its main metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol were eliminated slowly from the amniotic fluid, with levels still detectable up to 6 h after NNK treatment.

These results demonstrated that NNK instilled intratracheally in pregnant hamsters crossed the placental barrier even at low doses. Moreover, NNK quickly reached fetal tissues and amniotic fluid and was eliminated slowly from these tissues, resulting in an extended exposure of the fetus to this tobacco-specific carcinogen.

¹ Supported by National Cancer Institute Grant CA42829. 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 5/24/91. Accepted 4/ 6/92.

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