This Article Full Text 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 Begleiter, A. Articles by Bird, R. P. Search for Related Content PubMed PubMed Citation Articles by Begleiter, A. Articles by Bird, R. P.

Induction of NAD(P)H Quinone

Oxidoreductase1 Inhibits Carcinogen-induced Aberrant Crypt Foci in Colons of Sprague-Dawley Rats¹

Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Manitoba R3E 0V9 Canada [A. B., K. S.]; Departments of Internal Medicine [A. B., K. S.], Pharmacology and Therapeutics [A. B.], and Human Nutritional Sciences [R. P. B.], University of Manitoba, Winnipeg, Manitoba R3E 0V9 Canada; and Department of Pathology, Dartmouth College, Hanover, New Hampshire 03755 [T. J. C.]

Phase II detoxifying enzymes like NAD(P)H (quinone acceptor)oxidoreductase1 (NQO1), glutathione S-transferases (GST), and UDP-glucuronyltransferases (UGT) may play an important role in preventing carcinogen-induced cancers. Inducers of these enzymes have been shown to inhibit carcinogen-induced colon tumors in rat and mouse models. However, it has not been clearly demonstrated that NQO1 contributes to this effect. We examined the effect of NQO1 inducers on colon carcinogenesis using an aberrant crypt foci (ACF) rat model. Sprague-Dawley rats were fed control diet or diet containing 400 ppm dimethyl fumarate or 200 ppm oltipraz for 7 days, and Phase II enzymes in rat colon and liver were measured. Dimethyl fumarate significantly increased NQO1 and GST activities in colon and liver but did not increase UGT activities in these tissues. In contrast, oltipraz significantly increased NQO1 activities in colon and liver and produced a small increase in GST activity in the liver but did not increase GST activity in the colon or UGT activities in the liver or colon. Sprague Dawley rats were fed control diet or diet containing 200 ppm oltipraz and then treated with the carcinogens azoxymethane or methyl nitrosourea. Both carcinogens produced ACF in all of the rat colons, but rats fed oltipraz diet had significantly fewer ACF than those fed control diet. This protective effect was reversed in rats treated with the NQO1 inhibitor, dicoumarol. However, treatment with oltipraz did not alter the distribution of crypt multiplicities in the ACF. These studies demonstrated that induction of NQO1 plays a significant role in inhibiting initiation of carcinogen-induced ACF in Sprague-Dawley rats. This provides the first direct evidence that NQO1 may play a role in preventing colon cancer. The study also found that oltipraz added to the diet of Sprague-Dawley rats selectively increased NQO1 activity in colon mucosa with no increase in GST and UGT activities in these tissues. Thus, this model will be useful for further investigating the role of NQO1 in prevention of colon cancer.

This article has been cited by other articles:

				L. M. Aleksunes and J. E. Manautou Invited Review: Emerging Role of Nrf2 in Protecting Against Hepatic and Gastrointestinal Disease Toxicol Pathol, June 1, 2007; 35(4): 459 - 473. [Abstract] [PDF]

				A. Begleiter, D. Hewitt, A. W. Maksymiuk, D. A. Ross, and R. P. Bird A NAD(P)H:Quinone Oxidoreductase 1 Polymorphism Is a Risk Factor for Human Colon Cancer Cancer Epidemiol. Biomarkers Prev., December 1, 2006; 15(12): 2422 - 2426. [Abstract] [Full Text] [PDF]

				A. Piton, E. Le Ferrec, S. Langouet, C. Rauch, E. Petit, F. Le Goff, A. Guillouzo, and F. Morel Oltipraz regulates different categories of genes relevant to chemoprevention in human hepatocytes Carcinogenesis, February 1, 2005; 26(2): 343 - 351. [Abstract] [Full Text] [PDF]

				R. Munday and C. M. Munday Induction of phase II enzymes by 3H-1,2-dithiole-3-thione: dose-response study in rats Carcinogenesis, September 1, 2004; 25(9): 1721 - 1725. [Abstract] [Full Text] [PDF]

				Y. Zhang and G. B. Gordon A strategy for cancer prevention: Stimulation of the Nrf2-ARE signaling pathway Mol. Cancer Ther., July 1, 2004; 3(7): 885 - 893. [Abstract] [Full Text] [PDF]