Journal Article

DNA adduct formation, cell proliferation and aberrant crypt focus formation induced by PhIP in male and female rat colon with relevance to carcinogenesis

Masako Ochiai, Masatoshi Watanabe, Hiromi Kushida, Keiji Wakabayashi, Takashi Sugimura and Minako Nagao

in Carcinogenesis

Volume 17, issue 1, pages 95-98
Published in print January 1996 | ISSN: 0143-3334
e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/17.1.95
DNA adduct formation, cell proliferation and aberrant crypt focus formation induced by PhIP in male and female rat colon with relevance to carcinogenesis

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2-Amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP) induces colon tumors in male, but not female, F344 rats, We investigated the mechanisms leading to this difference by measuring the level of PhlP-DNA adducts, the enhancement of cell proliferation and aberrant crypt focus (ACF) formation in colon mucosa. PhIP was administered in the diet at a level of 0.04% to both male and female F344 rats for 1–8 weeks. The level of DNA adducts in the colon mucosa was measured using the 32P-postlabeling method. Four major PhlP-DNA adducts were detected in fairly constant proportions in all the animals examined. The level of PhlP-DNA adducts in male and female rats was the same, indicating no direct correlation between adduct levels and carcinogenesis. Labeling indices (LIs) were determined by measuring BrdU incorporation in rats after feeding with a PhIP diet for 4, 8 and 12 weeks. After 8 weeks administration the LI had increased 1.5-fold in the colon of the male rats, but no increase was observed in the female rats. ACF formation was examined after feeding with a PhIP diet for 14 weeks. The number of aberrant crypt foci was 6.6 ± 1.5 per rat in males and 1.9 ± 0.5 per rat in females. Thus differences in colon tumor development in male and female rats takes place at an early stage(s). Our results suggest that, in addition to DNA adduct formation, enhanced proliferation contribites to the formation of ACFs, which are premalignant lesions of the colon.

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Subjects: Clinical Cytogenetics and Molecular Genetics

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