| ABSTRACT: |
|
The ability of five chemopreventive agents to inhibit
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumors
in A/J mice was determined. The carcinogen was administered in the
drinking water during 7 weeks (at doses of 9.2 to 3.1 mg/mouse). Three
chemopreventive agents: (dose, g/kg diet) ellagic acid (4.0), 2(3)-BHA
(5.0), and sulindac (0.13) inhibited the multiplicity of lung adenomas by
52, 88, and 52%, respectively, when compared to NNK controls.
beta-Carotene + retinol (2.14 + 0.009), in combination, and selenium
(0.0022) were ineffective. NNK was absorbed more rapidly from the duodenum
than from the stomach and was metabolized in both tissues. The activation
of NNK by alpha-carbon hydroxylation and its deactivation by pyridine
N-oxidation was more extensive in the duodenum than in the stomach.
Carbonyl reduction of NNK was 10 times higher in the duodenum. Liver
microsomes were more active than lung microsomes in the alpha-carbon
hydroxylation of NNK, suggesting that some liver isozymes of cytochrome
P-450 have a high affinity for NNK. Pyridine N-oxidation was five times
more extensive in lung microsomes than in liver microsomes. Collectively,
these results demonstrate that NNK given orally to A/J mice provides a
suitable model from which to assess the relative activity and mechanisms
of action of chemopreventive agents in pulmonary carcinogenesis. |