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Dietary Selenite and Azadeoxycytidine Treatments Affect Dimethylhydrazine-Induced Aberrant Crypt Formation in Rat Colon and DNA Methylation in HT-29 Cells¹

U.S. Department of Agriculture, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202-9034

²To whom correspondence should be addressed. E-mail: cdavis{at}gfhnrc.ars.usda.gov.

Several observations implicate a role for altered DNA methylation in cancer pathogenesis. The global level of DNA methylation is generally lower; however, DNA methyltransferase (Dnmt1) activity is usually higher in tumor cells than in normal cells. The purpose of this study was to investigate whether the Dnmt1 inhibitor, 5-aza-2'-deoxycytidine (aza-dC) would alter the effect of dietary selenium on the formation of aberrant crypts. Weanling rats (n = 60) were fed three concentrations of selenium (deficient, 0.1 and 2.0 mg/kg diet) in a Torula yeast–based diet. Half of the rats were injected weekly with aza-dC (1 mg/kg, subcutaneously) and half were injected with the vehicle control (PBS). After 3.5 wk of consuming the experimental diets, the rats were given two injections of dimethylhydrazine (DMH; 25 mg/kg, intraperitoneally). Rats fed the selenium-deficient diet and injected with PBS had significantly (P < 0.006) more aberrant crypts than rats fed 0.1 or 2.0 mg selenium/kg diet (244 ± 21 vs. 165 ± 9 and 132 ± 14, respectively). In contrast, when rats were injected with aza-dC, there was a significant (P < 0.0001) reduction in aberrant crypt formation and dietary selenium had no effect (62 ± 8 vs. 77 ± 13 vs. 54 ± 8, in rats fed 0, 0.1 and 2.0 mg selenium/kg diet, respectively). HT-29 cells cultured in the absence of selenium had significantly hypomethylated DNA but significantly more Dnmt1 protein expression than cells cultured in the presence of 1 or 2 µmol/L selenium. These results suggest that aza-dC treatment may protect selenium-deficient rats against carcinogen-induced aberrant crypt formation.

KEY WORDS: • selenium • DNA methylation • azadeoxycytidine • HT-29 • DNA methyltransferase

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