Lung tumorigenicity of NNK given orally to A/J mice: its application to chemopreventive efficacy studies.
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.
Castonguay
A
A
Laboratory of Cancer Etiology and Chemoprevention, School of Pharmacy, Laval University, Quebec City, Canada.
Pepin
P
P
Stoner
G D
GD
D000236:Adenoma / Q000139:chemically induced / Q000517:prevention & control; D000284:Administration, Oral; D000818:Animals; D001681:Biological Assay; D002273:Carcinogens / Q000008:administration & dosage*; D004032:Diet; D007408:Intestinal Absorption / Q000502:physiology; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000517:prevention & control*; D051379:Mice; D008805:Mice, Inbred A; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D009602:Nitrosamines / Q000008:administration & dosage* / Q000037:antagonists & inhibitors*
D002273:Carcinogens; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone