DNA ADDUCT FORMATION, CELL-PROLIFERATION AND ABERRANT CRYPT FOCUS FORMATION INDUCED BY PHIP IN MALE AND FEMALE RAT COLON WITH RELEVANCE TO CARCINOGENESIS

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces colon t umors in male, but not female, F344 rats, We investigated the mechanis ms leading to this difference by measuring the level of PhIP-DNA adduc ts, the enhancement of cell proliferation and aberrant crypt focus (AC F) formation in colon mucosa. PhIP was administered in the diet at a l evel of 0.04% to both male and female F344 rats for 1-8 weeks. The lev el of DNA adducts in the colon mucosa was measured using the P-32-post labeling method. Four major PhIP-DNA adducts were detected in fairly c onstant proportions in all the animals examined, The level of PhIP-DNA adducts in male and female rats was the same, indicating no direct co rrelation between adduct levels and carcinogenesis, Labeling indices ( LIs) were determined by measuring BrdU incorporation in rats after fee ding with a PhIP diet for 4, 8 and 12 weeks, After 8 weeks administrat ion the LI had increased 1.5-fold in the colon of the male rats, but n o increase was observed in the female rats. ACF formation was examined after feeding with a PhIP diet for 14 weeks, The number of aberrant c rypt 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 femal e rats takes place at an early stage(s). Our results suggest that, in addition to DNA adduct formation, enhanced proliferation contributes t o the formation of ACFs, which are premalignant lesions of the colon.