Journal Article

Induction of tumors in the colon and liver of the immunodeficient (SCID) mouse by 2-amino-3-methylimidazo[4,5-<i>f</i> ]quinoline (IQ)—modulation by long-chain fatty acids

Elsayed I. Salim, Hideki Wanibuchi, Keiichirou Morimura, Takashi Murai, Susumu Makino, Taisei Nomura and Shoji Fukushima

in Carcinogenesis

Volume 23, issue 9, pages 1519-1529
Published in print September 2002 | ISSN: 0143-3334
Published online September 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.9.1519
Induction of tumors in the colon and liver of the immunodeficient (SCID) mouse by 2-amino-3-methylimidazo[4,5-f ]quinoline (IQ)—modulation by long-chain fatty acids

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We have recently shown that immunodeficient (SCID) mice, which lack functional T and B cells, are highly susceptible to low dose site specific induction of colon aberrant crypt foci (ACF), surrogates for colon tumors, by 2-amino-3-methylimidazo[4,5-f ]quinoline (IQ). To test whether long-term exposure to a high dose in the diet might prove carcinogenic to the SCID mouse colon, in contrast to other mice strains tested to date, the compound was administered at 300 p.p.m. in the diet to female 6–7-week-old SCID mice for 32 weeks. IQ induced high numbers of ACF, hyperplastic polyps, dysplasia, and colon adenomas, as well as hepatocellular altered foci and liver adenomas. Induction of colon tumors did not correlate with the main sites where ACF developed, the proximal colon, however, being seen mainly in the mid and distal colon. Induction of colon tumors correlated significantly with the incidence of dysplasia, crypt height, the mitotic index, cell proliferation and numbers of 8-hydroxydeoxyguanosine (8-OHdG)-positive cells in the colon crypt, particularly in mid and distal colon. Administration of 20% ωω-6 polyunsaturated fatty acids (corn oil), ωω-3 polyunsaturated fatty acids (perilla oil), or monounsaturated fatty acids (olive oil) simultaneously with IQ in the diet resulted in: (i) inhibition of colon and liver tumor induction by corn and perilla oil, whereas olive oil showed no effects; (ii) no reduction in total numbers of ACF by corn oil or perilla oil but significant suppression in the olive oil treated group; (iii) inhibition of tumor development particularly by ωω-3 polyunsaturated fatty acids in perilla oil, correlating significantly with decreased cell proliferation in both colon and liver and a marked decrease in crypt heights and mitotic indices. Selective reduction in the numbers of 8-OHdG-positive nuclei, mainly in the middle and distal colon crypts, was also found to correlate with tumor inhibition. Thus, the results indicate carcinogenicity of IQ in the colon of the SCID mouse and preventive effects of polyunsaturated fatty acids.

Keywords: ACF, aberrant crypt foci; DNA–PK, DNA-dependent protein kinase; HAAs, heterocyclic aromatic amines; 13-S-HODE, 13-S-hydroxyoctadecadienoic acid; IQ, 2-amino-3-methylimidazo[4,5-f]quinoline; 15-LOX, 15-lipoxygenase; MeIQx, 2-amino-3,8-methylimidazo[4,5-f]quinoxaline; 8-OHdG, 8-hydroxydeoxyguanosine; 7-OHIQ, N-hydroxyl IQ; PBS, phosphate buffered solution; PC, phosphatidylethanolamine; PUFAs, polyunsaturated fatty acids; PhIP, 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; SCID, severe combined immunodeficiency

Journal Article.  9173 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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