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Low levels of expression of cytochromes P-450 in normal and cancerous fetal pancreatic tissues of hamsters treated with NNK and/or ethanol.

Abstract
Previous studies from this laboratory have demonstrated that administration of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to pregnant hamsters results in tumors in the offspring. Whereas treatment with NNK alone caused mainly tumors in the respiratory tract of the treated offspring, cotreatment with ethanol (EtOH) and NNK shifted the site of tumor formation to the pancreas. In order to determine potential mechanisms for the cocarcinogenic effects of EtOH, the levels of NNK metabolites and expression of various CYPs implicated in the metabolic activation of NNK were determined in fetal liver and pancreas. NNK and its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), were detected at low and variable levels in the fetal liver and pancreas, with an NNAL to NNK ratio greater than 20 in both organs. EtOH had no effect on the amount of metabolites found in either organ. Results obtained with the fetal liver samples, which served as a positive control, correlated very well with our previous studies demonstrating low levels of expression of several CYP isozymes at both the protein and RNA level. Western blot analysis showed low but detectable levels of CYP1A1, barely detectable levels of CYP2E1, and an absence of CYP1A2 and 2B family members in the fetal pancreas. RNA transcripts were undetectable by ribonuclease protection in the fetal pancreas, although readily seen in fetal liver samples. Treatment with NNK, EtOH, or both NNK and EtOH had small and variable effects on the levels of metabolism of NNK and expression of the isozymes. These findings suggest that alternative mechanisms may be responsible for transplacentally induced tumors in this model system.
AuthorsL Zhang, D L Weddle, P E Thomas, B Zheng, A Castonguay, H M Schuller, M S Miller
JournalToxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 56 Issue 2 Pg. 313-23 (Aug 2000) ISSN: 1096-6080 [Print] United States
PMID10910989 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Carcinogens
  • DNA Adducts
  • Nitrosamines
  • Ethanol
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
  • Cytochrome P-450 Enzyme System
Topics
  • Animals
  • Blotting, Western
  • Carcinogens (toxicity)
  • Cricetinae
  • Cytochrome P-450 Enzyme System (biosynthesis)
  • DNA Adducts (analysis)
  • Ethanol (toxicity)
  • Female
  • Fetal Diseases (chemically induced, enzymology)
  • Liver (metabolism)
  • Mesocricetus
  • Nitrosamines (metabolism, toxicity)
  • Pancreas (metabolism)
  • Pancreatic Neoplasms (chemically induced, enzymology)
  • Pregnancy

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