Metabolism of azoxymethane, methylazoxymethanol and N -nitrosodimethylamine by cytochrome P450IIE1

Yoshida

et al. 2005

Intl Journal of Cancer

The effect of linoleic acid (LA) on growth and transformation of IEC6 intestinal cells was examined. IEC6 cells expressed mRNAs of 15-lipooxygenase (LOX15) and peroxisome proliferator-activated receptor (PPAR)c but not COX-2. Cell growth was suppressed by LA in a dose-dependent manner in IEC6 cells. Threeweek treatment with LA provided IEC6 cells a quiescent state. LA-induced growth inhibition was abrogated by exposure to antisense S-oligodeoxynucleotides (S-ODNs) for LOX15 and/or PPARc. In an in vitro carcinogenesis model, IEC6 cells, which had confirmed CYP2E1 expression and activity, were continuously treated with AOM and/or LA for 40 weeks. DNA injury in AOMtreated cells was suppressed to the control level by concurrent LA treatment. Colony formation of AOM-treated cells in soft agar was suppressed by treatment with LA, which was reversed by exposure to antisense S-ODNs for LOX15 and/or PPARc. AOMtreated IEC6 cells formed s.c. tumors in 9 of 12 mice, whereas AOM1LA-treated cells formed no tumor. IEC6 cells showed no remarkable alteration of protein production by AOM treatment, whereas cells treated with AOM1LA showed decreased epidermal growth factor receptor (EGFR) and phospho-EGFR and increased BAX. These findings suggest that LA inhibited AOMinduced transformation of COX-2-negative IEC6 cells, which was possibly mediated with PPARc ligands generated by LOX15 from LA. ' 2005 Wiley-Liss, Inc.Key words: linoleic acid; azoxymethane; colon cancer; transformation; peroxisome proliferator-activated receptor Colorectal cancer is the third most common malignant neoplasm worldwide and the third leading cause of cancer deaths in Japan. 1 The frequency of colon cancer in Japan is continuously increased along with the alteration of lifestyle from traditional Japanese to Western. In particular, the increase of fat intake and decrease of fiber intake have been regarded as the most important nutritional influence on colorectal cancer development. 2,3 Prostaglandins are bioactive lipids derived from the metabolites of membrane PUFAs and play important roles in a number of biologic processes. 4 COX-2-dependent overproduction of PGE 2 is hypothesized to be an important part of sustained proliferative and chronic inflammatory conditions. 5,6 Several in vivo studies hypothesize that a high amount of x-6 PUFA, such as LA, might enhance colorectal carcinogenesis via stimulation of colonic epithelial cell proliferation. 7-10 Indeed, rats treated with AOM and fed a diet supplemented with LA developed more tumors than animals treated with AOM alone. 11 AOM is a potent carcinogen, which induces colorectal cancers at high incidence in rats and mice. Adduct formation (mainly O 6 -methylguanine) by AOM induces point mutations in multiple genes such as K-ras and b-catenin. 12 In the present study, we used AOM as a carcinogen in the in vitro carcinogenesis model.The oxidative metabolites of LA, particularly 9-HODE, 13-HODE and 13-OXO, have biologic effects as PPARg ligands. 13 CLA, a strong ligand for PPARg, has a substantial anticarcin...

Section: Discussionsupporting

confidence: 55%

Inhibitory effect of linoleic acid on transformation of IEC6 intestinal cells by in vitro azoxymethane treatment

Yoshida

et al. 2005

Intl Journal of Cancer

Microbiology and Immunology

“…1). AOM is metabolized to methylazoxymethanol (MAM) (44) and is conjugated in the liver. Glucuronide conjugates of MAM are then excreted into the bile and deconjugated by bacterial β-glucuronidase (33).…”

Section: Discussionmentioning

confidence: 99%

Effects of High Amylose Maize Starch and Clostridium butyricum on Metabolism in Colonic Microbiota and Formation of Azoxymethane‐Induced Aberrant Crypt Foci in the Rat Colon

Nakanishi

Kataoka

Kuwahara

et al. 2003

High amylose maize starch (HAS) is not digested in the small intestine and most of it reaches the large intestine. In the large intestine, HAS is fermented by intestinal bacteria, resulting in production of short‐chain fatty acids (SCFA), particularly butyrate. Clostridium butyricum can utilize HAS and produce butyrate and acetate. It has been proposed that butyrate inhibits carcinogenesis in the colon. In this study, we examined the inhibitory effects of HAS and C. butyricum strain MIYAIRI588 (CBM588) on azoxymethane‐induced aberrant crypt foci (ACF) formation in rats. In the group of rats administered only CBM588 spores, the concentration of butyrate in the cecum increased, but there was no decrease in the number of ACF. In the group of rats fed an HAS diet, a decrease in the number of ACF was observed, and in the group of rats administered HAS and CBM588, the number of ACF decreased significantly. In these two groups, the concentrations of acetate and propionate in intestinal contents significantly increased, but the concentration of butyrate did not change. It was found that the β‐glucuronidase activity level of colonic contents decreased significantly in the two groups of rats fed HAS. This study showed that HAS and CBM588 changed the metabolism of colonic microbiota and decreased the level of β‐glucuronidase activity, phenomena that may play a role in the inhibition of ACF formation in the rat colon.

Asian Pacific Journal of Cancer Prevention

“…AOM is metabolized in the liver into MAM and this reaction is catalyzed by the enzyme cytochrome P450 E1 (Sohn et al, 1991). Metabolic activation of MAM to a highly reactive electrophile (methyl diazonium ion) occurs in liver and colon, which is known to elicit oxidative stress.…”

Section: Animal Models Of Cacmentioning

confidence: 99%

Signal Transducer and Activator of Transcription 3 - A Promising Target in Colitis-Associated Cancer

Pandurangan¹,

Esa²

2014

Colorectal cancer (CRC) is the third most common malignancy and fourth most common cause of cancer mortality worldwide. Untreated chronic inflammation in the intestine ranks among the top three high-risk conditions for colitis-associated colorectal cancer (CAC). Signal Transducer and Activator of Transcription 3 (STAT3) protein is a member of the STAT family of transcription factors often deregulated in CRC. In this review, we try to emphasize the critical role of STAT3 in CAC as well as the crosstalk of STAT3 with inflammatory cytokines, nuclear factor (NF)-κB, PI3K/Akt, Mammalian Target of Rapamycin (mTOR), Notch, Wnt/β-catenin and microRNA (MiR) pathways. STAT3 is considered as a primary drug target to treat CAC in humans and rodents. Also we updated the findings for inhibitors of STAT3 with regard to effeects on tumorigenesis. This review will hopefully provide insights on the use of STAT3 as a therapeutic target in CAC.