Beta-carotene interaction with NNK in the AJ-mouse model: effects on cell proliferation, tumor formation and retinoic acid responsive genes.
We studied the influence of beta-carotene on the tobacco smoke carcinogen 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumor development in the A/J-mouse model. The normally low beta-carotene absorption was facilitated with a diet enriched in fat and bile salt, resulting in plasma and lung tissue levels similar to humans. beta-Carotene enhanced NNK-induced early bronchial cell proliferation, however, this effect was not predictive for later tumor development. Tumor multiplicity was not significantly affected by beta-carotene, neither in carcinogen-initiated nor in uninitiated mice, and regardless of dose and time point of supplementation during tumor development. RARbeta isoform and CYP26 gene expression levels analyzed by quantitative RT-PCR were weakly, but significantly, inversely correlated and showed evidence for altered retinoid signaling and catabolism in the lungs of NNK-initiated, beta-carotene supplemented mice. However, this interaction did not translate into enhanced tumor multiplicity. These results indicate that impaired retinoid signaling is not likely a key factor in lung tumorigenesis in this mouse model.
Goralczyk
Regina
R
Build. 221/106, DSM Nutritional Products Ltd., R and D, Human Nutrition and Health P.O. Box 3255, CH-4002 Basel, Switzerland. regina.goralczyk@dsm.com
Wertz
Karin
K
Lenz
Barbara
B
Riss
Georges
G
Buchwald Hunziker
Petra
P
Geatrix
Brad
B
Aebischer
Claude-P
CP
Bachmann
Heinrich
H
D000236:Adenoma / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001980:Bronchi / Q000187:drug effects; D002273:Carcinogens; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D004347:Drug Interactions; D004847:Epithelial Cells / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D008168:Lung / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D009602:Nitrosamines; D020033:Protein Isoforms / Q000096:biosynthesis; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics; D000072516:Retinoic Acid 4-Hydroxylase; D019207:beta Carotene / Q000494:pharmacology*
D002273:Carcinogens; D009602:Nitrosamines; D020033:Protein Isoforms; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D019207:beta Carotene; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase