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
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
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DOI：
10.1002/mnfr.200900348
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发表时间：
2010-08-01
影响因子：
5.2
通讯作者：
Itoh, Makoto
中科院分区：
文献类型：
--
作者：
Ishikawa, Shin-ichi;Tamaki, Satoru;Itoh, Makoto
流行病学和动物模型研究表明，红肉中血红素的高摄入量与结肠癌风险增加有关。然而，这种关联的机制尚不清楚。本研究旨在探讨血红素是否通过血红素加氧酶（HO）产生过氧化氢诱导结肠上皮细胞DNA损伤和细胞增殖。我们研究了锌原卟啉（ZnPP; HO抑制剂）和过氧化氢酶对DNA损伤，细胞增殖和IL-8的产生诱导的氯化血红素（1-10 μ M）加入人结肠上皮Caco-2细胞的影响。彗星试验检测DNA损伤，5-溴-2 '-脱氧尿苷掺入试验检测细胞增殖。ZnPP和外源性过氧化氢酶均能抑制氯化血红素诱导的DNA损伤和细胞过度增殖，并呈剂量依赖性。IL-8 mRNA的表达和IL-8在上皮细胞中的产生增加后，氯化血红素处理，但生产的抑制ZnPP和过氧化氢酶。这些结果表明，氯化血红素具有遗传毒性和过度增殖的Caco-2细胞的HO和过氧化氢的影响。这一机制可能解释了为什么大量摄入血红素与结肠癌风险增加有关。
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 mu M) 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.