de Vogel Johan, van-Eck Wytske Boersma, Sesink Aloys L A, Jonker-Termont Denise S M L, Kleibeuker Jan, van der Meer Roelof
TI Food and Nutrition, PO Box 557, 6700 AN Wageningen, The Netherlands.
Carcinogenesis. 2008 Feb;29(2):398-403. doi: 10.1093/carcin/bgm278. Epub 2008 Jan 3.
Epidemiological and animal model studies suggest that a high intake of heme, present in red meat, is associated with an increased risk of colon cancer. The aim of this study was to elucidate the effects of dietary heme on colonic cell homeostasis in rats. Rats were fed a purified, humanized, control diet or a similar diet supplemented with 0.5 mmol heme/kg for 14 days. Fecal water cytolytic activity was determined with a bioassay, and colon epithelial cell proliferation was evaluated with (3)H-thymidine or 5-bromo-2'-deoxyuridine incorporation into DNA or by Ki-67 immunohistochemistry. Exfoliation of colonocytes was measured as the amount of rat DNA in feces, and caspase-3 expression and activity were measured to study colonic mucosal apoptosis. Dietary heme induced a >10-fold increased cytolytic activity of the fecal water and a 100-fold lower excretion of host DNA. Colons of heme-fed rats showed injured surface epithelium and an approximately 25% increase in crypt depth. Finally, dietary heme doubled colonocyte proliferation, shown by all three markers, but inhibited colonic mucosal apoptosis. In conclusion, our results demonstrate that dietary heme injures colonic surface epithelium, which is overcompensated by inhibition of apoptosis and hyperproliferation of cells in the crypts, resulting in crypt hyperplasia. This disturbed epithelial cell homeostasis might explain why a high intake of dietary heme is associated with an increased risk of colon cancer.
流行病学和动物模型研究表明，红肉中所含的高血红素摄入量与结肠癌风险增加有关。本研究的目的是阐明膳食血红素对大鼠结肠细胞内稳态的影响。将大鼠喂食纯化的、人性化的对照饮食或补充有0.5 mmol血红素/千克的类似饮食14天。用生物测定法测定粪便水细胞溶解活性，并用（3）H-胸腺嘧啶核苷或5-溴-2'-脱氧尿苷掺入DNA或通过Ki-67免疫组织化学评估结肠上皮细胞增殖。将结肠细胞的脱落作为粪便中大鼠DNA的量来测量，并测量caspase-3的表达和活性以研究结肠黏膜凋亡。膳食血红素使粪便水的细胞溶解活性增加了10倍以上，宿主DNA的排泄量降低了100倍。喂食血红素的大鼠结肠显示表面上皮受损，隐窝深度增加约25%。最后，膳食血红素使结肠细胞增殖增加了一倍，这由所有三种标志物显示，但抑制了结肠黏膜凋亡。总之，我们的结果表明，膳食血红素会损伤结肠表面上皮，而隐窝中细胞凋亡的抑制和过度增殖会对此进行过度补偿，导致隐窝增生。这种上皮细胞内稳态的紊乱可能解释了为什么高膳食血红素摄入量与结肠癌风险增加有关。
