title: Heme induces DNA damage and hyperproliferation of colonic epithelial cells via hydrogen peroxide produced by heme oxygenase: a possible mechanism of heme-induced colon cancer.
abstract: Epidemiological and animal model studies have suggested that high intake of heme, present in red meat, is associated with an increased risk of colon cancer. However, the mechanisms underlying this association are not clear. This study aimed to investigate whether heme induces DNA damage and cell proliferation of colonic epithelial cells via hydrogen peroxide produced by heme oxygenase (HO). We examined the effects of zinc protoporphyrin (ZnPP; a HO inhibitor) and catalase on DNA damage, cell proliferation, and IL-8 production induced by the addition of hemin (1-10 microM) to human colonic epithelial Caco-2 cells. DNA damage was determined with a comet assay, and cell proliferation was evaluated with 5-bromo-2'-deoxyuridine incorporation assay. Both ZnPP and exogenous catalase inhibited the hemin-induced DNA damage and cell hyperproliferation dose-dependently. IL-8 messenger RNA expression and IL-8 production in the epithelial cells increased following the hemin treatment, but the production was inhibited by ZnPP and catalase. These results indicate that hemin has genotoxic and hyperproliferative effects on Caco-2 cells by HO and hydrogen peroxide. The mechanism might explain why a high intake of heme is associated with increased risk of colon cancer.
authors.affiliation: Department of Animal Science, School of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan. ishikawa@vmas.kitasato-u.ac.jp
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Satoru
authors.initials: S
authors.lastname: Tamaki
authors.forename: Motoko
authors.initials: M
authors.lastname: Ohata
authors.forename: Keizo
authors.initials: K
authors.lastname: Arihara
authors.forename: Makoto
authors.initials: M
authors.lastname: Itoh
mesh_terms: D018938:Caco-2 Cells; D002374:Catalase / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000453:epidemiology / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006418:Heme / Q000378:metabolism / Q000633:toxicity*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008460:Meat / Q000009:adverse effects; D009994:Osmolar Concentration; D018384:Oxidative Stress / Q000187:drug effects; D011524:Protoporphyrins / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors
chemical_list: C508606:CXCL8 protein, human; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D011524:Protoporphyrins; D012333:RNA, Messenger; C017803:zinc protoporphyrin; D006418:Heme; D006861:Hydrogen Peroxide; D002374:Catalase; D006419:Heme Oxygenase (Decyclizing)