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.