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Research ArticleArticle

Investigation of the Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone for In Vivoand In Vitro Murine Embryopathy and Embryonic rasMutations

Louise M. Winn, Perry M. Kim and Peter G. Wells
Journal of Pharmacology and Experimental Therapeutics December 1998, 287 (3) 1128-1135;
Louise M. Winn
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Perry M. Kim
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Peter G. Wells
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Abstract

The teratological potential of the carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is unknown.In vivo, NNK (100 mg/kg i.p.) was administered to pregnant CD-1 mice during organogenesis, with or without pretreatment with the P450 inducer phenobarbital (60 mg/kg i.p.). With NNK alone, 3 of 374 fetuses had open eye and one had a cleft palate, which were not observed in 160 controls. With phenobarbital plus NNK, two fetuses had a cleft palate, two had exencephaly and one had a kinky tail, although phenobarbital controls showed no anomalies (P < .05). NNK-initiated fetal postpartum lethality was enhanced by phenobarbital pretreatment. There were no fetal skeletal anomalies or alterations in resorptions or fetal body weight in any group. In embryo culture, gestational day 9.5 embryos exposed to 10 μM NNK had decreases in yolk sac diameter, crown-rump length and somite development (P < .05), and 100 μM NNK decreased anterior neuropore closure and crown-rump length (P < .05). Embryos exposed to 100 μM NNK were assessed for K-ras codon 12 mutations and none were detected. This is the first evidence for NNK teratogenicity and embryotoxicity, the molecular mechanism of which appears to differ from that for its carcinogenicity.

Footnotes

  • Send reprint requests to: Dr. Peter G. Wells, Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario, Canada M5S 2S2.

  • ↵1 A preliminary report was presented at the 35th annual meeting of the Society of Toxicology (Fundam Appl Toxicol30(Suppl. No. 1, Part 2): 198, 1996). This research was supported by a grant from the Medical Research Council of Canada.

  • Abbreviations:
    CYP
    cytochrome P450
    DMSO
    dimethyl sulphoxide
    GD
    gestational day
    NNAL
    4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol
    NNK
    4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
    P450
    cytochromes P450
    PAH
    polycyclic aromatic hydrocarbon
    PHS
    prostaglandin H synthase
    ROS
    reactive oxygen species
    SOD
    superoxide dismutase
    UGT
    UDP-glucuronosyltransferase
    PCR
    polymerase chain reaction
    BP
    benzo[a]pyrene
    • Received April 16, 1998.
    • Accepted July 10, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 3
1 Dec 1998
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Research ArticleArticle

Investigation of the Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone for In Vivoand In Vitro Murine Embryopathy and Embryonic rasMutations

Louise M. Winn, Perry M. Kim and Peter G. Wells
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 1128-1135;

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Research ArticleArticle

Investigation of the Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone for In Vivoand In Vitro Murine Embryopathy and Embryonic rasMutations

Louise M. Winn, Perry M. Kim and Peter G. Wells
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 1128-1135;
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