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.

Red meat and colon cancer: Should we become vegetarians, or can we make meat safer?

“…This mechanism has received limited support from studies on cancer cells in vitro. They show that hemin induces DNA damage in human cells of colonic origin (Glei, et al, 2006), via hydrogen peroxide produced by hemeoxygenase, which can be inhibited in vitro by Zn-protoporphyrin (Ishikawa, Tamaki, Ohata, Arihara, & Itoh, 2010).…”

Identifying Molecular Targets of Lifestyle Modifications in Colon Cancer Prevention

“…White meat is not associated with an increased risk of CRC, so what dietary factor/s in red meat increases the risk of cancer development? One important dietary factor could be heme, an iron porphyrin pigment of red meat, present 10-fold higher in red meat compared to white meat (Schwartz and Ellefson, 1985; Ishikawa et al, 2010). A free ferrous iron is released when heme oxygenase-1 (HO-1) resolves dietary heme in the intestinal mucosa (Ishikawa et al, 2010).…”

Development of a heme sensor using fluorescently labeled heme oxygenase-1

“…Free heme (protein-unbound heme) is known as a prooxidant molecule that can catalyze production of reactive oxygen species and may potentially cause oxidative damage to cells and tissues [3,4]. Free heme is also reported to be involved in the progression of several disorders such as colon cancer [5] and Alzheimer's disease [6,7]. In addition to its toxic effects, recent studies reveal that free heme has regulatory effects on various cellular events, including gene transcription [8], ion channel control [9], microRNA processing [10], and circadian regulation [11,12].…”