This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morse, M. A. Articles by Chung, F.-L. Search for Related Content PubMed PubMed Citation Articles by Morse, M. A. Articles by Chung, F.-L.

Effects of Indole-3-carbinol on Lung Tumorigenesis and DNA Methylation Induced by 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and on the Metabolism and Disposition of NNK in A/J Mice¹

Section of Nucleic Acid Chemistry, Division of Chemical Carcinogenesis, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York 10595

The effects of indole-3-carbinol (13C) on lung neoplasia induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were assessed in an A/J mouse pulmonary adenoma bioassay. Mice were administered corn oil or I3C (25 or 125 µmol/mouse/day) by gavage for 4 consecutive days. Two h after the final pretreatment, mice were administered a single dose of NNK (10 µmol/mouse) i.p. Pulmonary adenomas were quantitated 16 wk after NNK dosing. Mice pretreated with corn oil developed 10.7 tumors/mouse; I3C pretreatment at either dose level inhibited tumor multiplicity by approximately 40%. The effects of I3C on NNK-induced DNA methylation in the lungs and livers of A/J mice were assessed using the same dosing regimen as in the bioassay. Both dose levels of I3C inhibited pulmonary O⁶-methylguanine formation by at least 50%, but enhanced hepatic DNA methylation at 2 or at 6 h after NNK administration. The effects of I3C pretreatment on NNK metabolism were also investigated. Hepatic microsomes of I3C-pretreated mice showed increased formation of -hydroxylation products, while no significant effect of I3C pretreatment was observed in pulmonary microsomes. The effects of I3C on [5-³H]NNK disposition were also evaluated. I3C pretreatment produced lower levels of total radioactivity in the lung when compared with controls. Additionally, lower proportions of NNK and its carcinogenic metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol were found in the lungs of I3C-pretreated mice. These results demonstrate that I3C inhibits NNK-induced lung neoplasia in A/J mice and suggest that the basis of this inhibition is the decrease in O⁶-methylguanine formation in A/J lung caused by I3C pretreatment. This decrease in lung DNA methylation appears to be due to the decreased bioavailability of NNK and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in the lungs of I3C-treated mice which, in turn, may be a result of increased metabolic -hydroxylation of NNK by the liver.

¹ This is Paper 8 in "Dietary Inhibitors of Chemical Carcinogenesis." This work was supported by National Cancer Institute Grant CA 41544.

² To whom requests for reprints should be addressed.

Received 7/ 7/89. Revised 11/ 6/89.

This article has been cited by other articles:

				Y. Weng, C. Fang, R. J. Turesky, M. Behr, L. S. Kaminsky, and X. Ding Determination of the Role of Target Tissue Metabolism in Lung Carcinogenesis Using Conditional Cytochrome P450 Reductase-Null Mice Cancer Res., August 15, 2007; 67(16): 7825 - 7832. [Abstract] [Full Text] [PDF]

				F. Kassie, L. B. Anderson, R. Scherber, N. Yu, D. Lahti, P. Upadhyaya, and S. S. Hecht Indole-3-carbinol Inhibits 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Plus Benzo(a)pyrene-Induced Lung Tumorigenesis in A/J Mice and Modulates Carcinogen-Induced Alterations in Protein Levels Cancer Res., July 1, 2007; 67(13): 6502 - 6511. [Abstract] [Full Text] [PDF]

				S. C. Tilton, J. D. Hendricks, G. A. Orner, C. B. Pereira, G. S. Bailey, and D. E. Williams Gene expression analysis during tumor enhancement by the dietary phytochemical, 3,3'-diindolylmethane, in rainbow trout Carcinogenesis, July 1, 2007; 28(7): 1589 - 1598. [Abstract] [Full Text] [PDF]

				J. H. Fowke, J. D. Morrow, S. Motley, R. M. Bostick, and R. M. Ness Brassica vegetable consumption reduces urinary F2-isoprostane levels independent of micronutrient intake Carcinogenesis, October 1, 2006; 27(10): 2096 - 2102. [Abstract] [Full Text] [PDF]

				J. C. Hsu, J. Zhang, A. Dev, A. Wing, L. F. Bjeldanes, and G. L. Firestone Indole-3-carbinol inhibition of androgen receptor expression and downregulation of androgen responsiveness in human prostate cancer cells Carcinogenesis, November 1, 2005; 26(11): 1896 - 1904. [Abstract] [Full Text] [PDF]

				Y. Takada, M. Andreeff, and B. B. Aggarwal Indole-3-carbinol suppresses NF-{kappa}B and I{kappa}B{alpha} kinase activation, causing inhibition of expression of NF-{kappa}B-regulated antiapoptotic and metastatic gene products and enhancement of apoptosis in myeloid and leukemia cells Blood, July 15, 2005; 106(2): 641 - 649. [Abstract] [Full Text] [PDF]

				H. H. Garcia, G. A. Brar, D. H. H. Nguyen, L. F. Bjeldanes, and G. L. Firestone Indole-3-Carbinol (I3C) Inhibits Cyclin-dependent Kinase-2 Function in Human Breast Cancer Cells by Regulating the Size Distribution, Associated Cyclin E Forms, and Subcellular Localization of the CDK2 Protein Complex J. Biol. Chem., March 11, 2005; 280(10): 8756 - 8764. [Abstract] [Full Text] [PDF]

				M. J. Anderton, M. M. Manson, R. D. Verschoyle, A. Gescher, J. H. Lamb, P. B. Farmer, W. P. Steward, and M. L. Williams Pharmacokinetics and Tissue Disposition of Indole-3-carbinol and Its Acid Condensation Products after Oral Administration to Mice Clin. Cancer Res., August 1, 2004; 10(15): 5233 - 5241. [Abstract] [Full Text] [PDF]

				S. S. Hecht, S. G. Carmella, P. M.J. Kenney, S.-H. Low, K. Arakawa, and M. C. Yu Effects of Cruciferous Vegetable Consumption on Urinary Metabolites of the Tobacco-Specific Lung Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Singapore Chinese Cancer Epidemiol. Biomarkers Prev., June 1, 2004; 13(6): 997 - 1004. [Abstract] [Full Text] [PDF]

				Y. Shukla, B. Srivastava, A. Arora, and L K. Chauhan Protective effects of indole-3-carbinol on cyclophosphamide-induced clastogenecity in mouse bone marrow cells Human and Experimental Toxicology, May 1, 2004; 23(5): 245 - 250. [Abstract] [PDF]

				G. L. Firestone and L. F. Bjeldanes Indole-3-Carbinol and 3-3'-Diindolylmethane Antiproliferative Signaling Pathways Control Cell-Cycle Gene Transcription in Human Breast Cancer Cells by Regulating Promoter-Sp1 Transcription Factor Interactions J. Nutr., July 1, 2003; 133(7): 2448S - 2455. [Abstract] [Full Text] [PDF]

				D. E. Williams, G. S. Bailey, A. Reddy, J. D. Hendricks, A. Oganesian, G. A. Orner, C. B. Pereira, and J. A. Swenberg The Rainbow Trout (Oncorhynchus mykiss) Tumor Model: Recent Applications in Low-Dose Exposures to Tumor Initiators and Promoters Toxicol Pathol, January 1, 2003; 31(1_suppl): 58 - 61. [Abstract] [PDF]

				G. Stoner, B. Casto, S. Ralston, B. Roebuck, C. Pereira, and G. Bailey Development of a multi-organ rat model for evaluating chemopreventive agents: efficacy of indole-3-carbinol Carcinogenesis, February 1, 2002; 23(2): 265 - 272. [Abstract] [Full Text] [PDF]

				S. Katchamart, D. M. Stresser, S. S. Dehal, D. Kupfer, and D. E. Williams Concurrent Flavin-Containing Monooxygenase Down-Regulation and Cytochrome P-450 Induction by Dietary Indoles in Rat: Implications for Drug-Drug Interaction Drug Metab. Dispos., August 1, 2000; 28(8): 930 - 936. [Abstract] [Full Text]

				J. W Lampe Health effects of vegetables and fruit: assessing mechanisms of action in human experimental studies Am. J. Clinical Nutrition, September 1, 1999; 70(3): 475S - 490. [Abstract] [Full Text] [PDF]

				A. Oganesian, J. D. Hendricks, C. B. Pereira, G. A. Orner, G. S. Baileyand, and D. E. Williams Potency of dietary indole-3-carbinol as a promoter of aflatoxin B1-initiated hepatocarcinogenesis: results from a 9000 animal tumor study Carcinogenesis, March 1, 1999; 20(3): 453 - 458. [Abstract] [Full Text] [PDF]

				C. M. Cover, S. J. Hsieh, E. J. Cram, C. Hong, J. E. Riby, L. F. Bjeldanes, and G. L. Firestone Indole-3-Carbinol and Tamoxifen Cooperate to Arrest the Cell Cycle of MCF-7 Human Breast Cancer Cells Cancer Res., March 1, 1999; 59(6): 1244 - 1251. [Abstract] [Full Text] [PDF]

				C. M. Cover, S. J. Hsieh, S. H. Tran, G. Hallden, G. S. Kim, L. F. Bjeldanes, and G. L. Firestone Indole-3-carbinol Inhibits the Expression of Cyclin-dependent Kinase-6 and Induces a G1 Cell Cycle Arrest of Human Breast Cancer Cells Independent of Estrogen Receptor Signaling J. Biol. Chem., February 13, 1998; 273(7): 3838 - 3847. [Abstract] [Full Text] [PDF]