Red meat and colon cancer: The cytotoxic and hyperproliferative effects ofdietary heme

The intake of a Western diet with a high amount of red meat is associated w ith a high risk for colon cancer. We hypothesize that heme, the iron carrie r of red meat, is involved in diet-induced colonic epithelial damage, resul ting in increased epithelial proliferation. Rats were fed purified control diets, or purified diets supplemented with 1.3 mu mol/g of hemin (ferriheme ), protoporphyrin LY, ferric citrate, or bilirubin (rt = 8/group) for 14 da ys. Feces were collected for biochemical analyses. Fecal cytotoxicity was d etermined from the degree of lysis of erythrocytes by fecal water. Colonic epithelial proliferation was measured in vivo using [H-3]thymidine incorpor ation into colonic mucosa. The colonic epithelial proliferation in heme-fed rats was significantly inc reased compared to control rats [55.2 +/- 5.8 versus 32.6 +/- 6.3 dpm/mu g DNA (mean +/- SE); P < 0.05]. The fecal water of the heme group was highly cytotoxic compared to the controls (90 +/- 2% versus 2 +/- 1%; P < 0.001), although the concentrations of cytotoxic bile acids and fatty acids were si gnificantly lower. Organic iron was significantly increased compared to the controls (257 +/- 26 versus 80 +/- 21 mu M; P < 0.001). Spectrophotometric analyses suggest that this organic iron is heme-associated, Thiobarbituric acid-reactive substances were greatly increased in the fecal water of heme -fed rats compared to the controls (177 +/- 12 versus 59 +/- 7 mu M; P < 0. 05), Heme itself could not account for the increased cytotoxicity. because the addition of heme to the fecal water of the control group, which was equ imolar to the organic iron content of the fecal water of the heme group, di d not influence the cytotoxicity. Hence, an additional heme-induced cytotox ic factor is involved, which may be modulated by the generation of luminal- reactive oxygen species. Protoporphyrin IX, ferric citrate, and bilirubin d id not increase proliferation and cytotoxicity. In conclusion, dietary heme leads to the formation of an unknown, highly cytotoxic factor in the colon ic lumen. This suggests that, in heme-fed rats, colonic mucosa is damaged b y the intestinal contents, This results in a compensatory hyperproliferatio n of the epithelium, which supposedly increases the risk for colon cancer.