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Carcinogenesis Advance Access originally published online on January 3, 2008
Carcinogenesis 2008 29(2):398-403; doi:10.1093/carcin/bgm278
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Dietary heme injures surface epithelium resulting in hyperproliferation, inhibition of apoptosis and crypt hyperplasia in rat colon

Johan de Vogel1,2, Wytske Boersma van-Eck3, Aloys L.A. Sesink1, Denise S.M.L. Jonker-Termont1,2, Jan Kleibeuker3 and Roelof van der Meer1,2,*

1 TI Food and Nutrition, PO Box 557, 6700 AN Wageningen, The Netherlands
2 NIZO Food Research, PO Box 20, 6710 BA Ede, The Netherlands
3 Department of Gastroenterology, University Medical Centre Groningen, PO Box 3001, 9700 RB Groningen, The Netherlands

* To whom correspondence should be addressed. Tel: +31 318 659559; Fax: +31 318 650400; Email: roelof.van.der.meer{at}nizo.nl

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 3H-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 ~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.

Abbreviations: BrdU, 5-bromo-2'-deoxyuridine; BSA, bovine serum albumin; DMSO, dimethyl sulfoxide; PBS, phosphate-buffered saline; TBS-T, Tris-buffered saline–Tween

Received June 21, 2007; revised December 4, 2007; accepted December 4, 2007.


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