Antioxidant effects of flavonoids used as food additives (purple corn color, enzymatically modified isoquercitrin, and isoquercitrin) on liver carcinogenesis in a rat medium-term bioassay.

To clarify the effects of purple corn color, enzymatically modified isoquercitrin (EMIQ), and isoquercitrin (IQ), registered as natural food additives in Japan, on liver carcinogenesis in vivo, a medium-term bioassay was employed. A total of 100 male F344 rats were divided into 5 groups; groups 1 to 4 were given a single intraperitoneal injection of diethylnitrosamine (200 mg/kg b.w.) on day 1. From weeks 2 to 8, they were administered basal diet purple corn color, EMIQ, or IQ as containing test chemicals at doses of 1.0% (groups 1 and 5), 0.1% (group 2), 0.01% (group 3), or 0% (group 4) (experiments 1, 4, and 5). All rats were subjected to two-thirds partial hepatectomy at week 3 and were sacrificed at week 8. Purple corn color exerted no significant modifying effects on GST-P positive foci, preneoplastic foci, development in the liver. However, serum of rats treated with purple corn color provided evidence of antioxidant power significantly by potential antioxidant (PAO) test in vivo (experiment 2). And microarray analyses showed purple corn color to induce RNA expression such as P450 (cytochrome) oxidoreductase, phosphatidylinositol 3-kinase, and phospholipase A2 (experiment 3). Higher doses of EMIQ or IQ with strong antioxidant power in vivo by PAO test treated groups were correlated with smaller numbers of GST-P positive foci, with Spearman's rank correlation coefficients of P= 0.002 and P= 0.049, respectively (experiments 4 and 5). Therefore, the tested food additives may be effective as antioxidants in vivo and have chemopreventive potential against liver preneoplastic lesion development.

[1]  U. Kaindl,et al.  The dietary antioxidants resveratrol and quercetin protect cells from exogenous pro-oxidative damage. , 2008, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[2]  A. Monabati,et al.  Protective effects of a combination of quercetin and vitamin E against cyclosporine A‐induced oxidative stress and hepatotoxicity in rats , 2008, Hepatology research : the official journal of the Japan Society of Hepatology.

[3]  Sonia Ramos,et al.  Effects of dietary flavonoids on apoptotic pathways related to cancer chemoprevention. , 2007, The Journal of nutritional biochemistry.

[4]  M. Moriwaki,et al.  Effect of enzymatically modified isoquercitrin in spontaneously hypertensive rats. , 2007, Journal of nutritional science and vitaminology.

[5]  A. Abe,et al.  Effects of dietary administration of plant-derived anthocyanin-rich colors to spontaneously hypertensive rats. , 2007, Journal of nutritional science and vitaminology.

[6]  G. Beecher,et al.  Concentrations of anthocyanins in common foods in the United States and estimation of normal consumption. , 2006, Journal of agricultural and food chemistry.

[7]  K. Stangl,et al.  The role of tea and tea flavonoids in cardiovascular health. , 2006, Molecular nutrition & food research.

[8]  Yuling Zhang.  Protective effect of quercetin on aroclor 1254-induced oxidative damage in cultured chicken spermatogonial cells. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[9]  P. Rapisarda,et al.  Anthocyanins accumulation and related gene expression in red orange fruit induced by low temperature storage. , 2005, Journal of agricultural and food chemistry.

[10]  P. Matarrese,et al.  Oxidative imbalance and cathepsin D changes as peripheral blood biomarkers of Alzheimer disease: A pilot study , 2005, FEBS letters.

[11]  M. Kano,et al.  Antioxidative Activity of Anthocyanins from Purple Sweet Potato, Ipomoera batatas Cultivar Ayamurasaki , 2005, Bioscience, biotechnology, and biochemistry.

[12]  M. Kaneko,et al.  Lack of carcinogenicity of enzymatically modified isoquercitrin in F344/DuCrj rats. , 2004, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[13]  G. C. Zucchelli,et al.  Oxidative stress and its association with coronary artery disease and different atherogenic risk factors , 2004, Journal of internal medicine.

[14]  A. Sengupta,et al.  Comparative evaluation of cancer chemopreventive efficacy of alpha-tocopherol and quercetin in a murine model. , 2004, Journal of experimental & clinical cancer research : CR.

[15]  Tomoyuki Shirai,et al.  Rapid analysis of gene expression changes caused by liver carcinogens and chemopreventive agents using a newly developed three‐dimensional microarray system , 2004, Cancer science.

[16]  R. Aalinkeel,et al.  Inhibition of Prostate Cancer Cell Colony Formation by the Flavonoid Quercetin Correlates with Modulation of Specific Regulatory Genes , 2004, Clinical Diagnostic Laboratory Immunology.

[17]  Dean P. Jones,et al.  Diet and apoptosis. , 2003, Annual review of nutrition.

[18]  De-Xing Hou,et al.  Anthocyanidins inhibit activator protein 1 activity and cell transformation: structure-activity relationship and molecular mechanisms. , 2003, Carcinogenesis.

[19]  S. Fukushima,et al.  Phenobarbital at low dose exerts hormesis in rat hepatocarcinogenesis by reducing oxidative DNA damage, altering cell proliferation, apoptosis and gene expression. , 2003, Carcinogenesis.

[20]  De-Xing Hou,et al.  Potential mechanisms of cancer chemoprevention by anthocyanins. , 2003, Current molecular medicine.

[21]  K. Imaida,et al.  Prevention by natural food anthocyanins, purple sweet potato color and red cabbage color, of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-associated colorectal carcinogenesis in rats initiated with 1,2-dimethylhydrazine. , 2002, The Journal of toxicological sciences.

[22]  T. Tsukamoto,et al.  Differential Effects of Partial Hepatectomy and Carbon Tetrachloride Administration on Induction of Liver Cell Foci in a Model for Detection of Initiation Activity , 2001, Japanese journal of cancer research : Gann.

[23]  K. Imaida,et al.  Pronounced inhibition by a natural anthocyanin, purple corn color, of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-associated colorectal carcinogenesis in male F344 rats pretreated with 1,2-dimethylhydrazine. , 2001, Cancer letters.

[24]  S. Joshi,et al.  Chemopreventive effects of grape seed proanthocyanidin extract on Chang liver cells. , 2000, Toxicology.

[25]  H. Daniel,et al.  Dietary flavone is a potent apoptosis inducer in human colon carcinoma cells. , 2000, Cancer research.

[26]  S. Toyokuni,et al.  Overexpression of the hOGG1 gene and high 8-hydroxy-2'-deoxyguanosine (8-OHdG) lyase activity in human colorectal carcinoma: regulation mechanism of the 8-OHdG level in DNA. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[27]  L. Marnett,et al.  Oxyradicals and DNA damage. , 2000, Carcinogenesis.

[28]  R. Agarwal,et al.  A flavonoid antioxidant, silymarin, inhibits activation of erbB1 signaling and induces cyclin-dependent kinase inhibitors, G1 arrest, and anticarcinogenic effects in human prostate carcinoma DU145 cells. , 1998, Cancer research.

[29]  R. Agarwal,et al.  Anticarcinogenic effect of a flavonoid antioxidant, silymarin, in human breast cancer cells MDA-MB 468: induction of G1 arrest through an increase in Cip1/p21 concomitant with a decrease in kinase activity of cyclin-dependent kinases and associated cyclins. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[30]  T. Shirai,et al.  Studies of initiation and promotion of carcinogenesis by N-nitroso compounds. , 1998, Cancer letters.

[31]  Y. Hashimoto,et al.  Antitumor effect of anthocyanin fractions extracted from red soybeans and red beans in vitro and in vivo. , 1997, Cancer biotherapy & radiopharmaceuticals.

[32]  S. Kuo.  Antiproliferative potency of structurally distinct dietary flavonoids on human colon cancer cells. , 1996, Cancer letters.

[33]  Y. Hashimoto,et al.  Antitumor effect of hydrolyzed anthocyanin from grape rinds and red rice. , 1996, Cancer biotherapy & radiopharmaceuticals.

[34]  K. Singletary,et al.  In vitro anticancer activity of fruit extracts from Vaccinium species. , 1996, Planta medica.

[35]  N Ito,et al.  Medium-term liver and multi-organ carcinogenesis bioassays for carcinogens and chemopreventive agents. , 1996, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[36]  W. Regelson,et al.  Review of the biology of Quercetin and related bioflavonoids. , 1995, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[37]  T. Holton,et al.  Genetics and Biochemistry of Anthocyanin Biosynthesis. , 1995, The Plant cell.

[38]  G. Mazza,et al.  Anthocyanins in grapes and grape products. , 1995, Critical reviews in food science and nutrition.

[39]  Takeshi Mori,et al.  IPAP: IMAGE PROCESSOR FOR ANALYTICAL PATHOLOGY , 1994 .

[40]  N Ito,et al.  Enhancing effect of various hepatocarcinogens on induction of preneoplastic glutathione S-transferase placental form positive foci in rats--an approach for a new medium-term bioassay system. , 1988, Carcinogenesis.

[41]  M. Tatematsu,et al.  The effects of various chemicals on the development of hyperplastic liver nodules in hepatectomized rats treated with N-nitrosodiethylamine or N-2-fluorenylacetamide. , 1980, Gan.

[42]  E Farber,et al.  Induction of resistant hepatocytes as a new principle for a possible short-term in vivo test for carcinogens. , 1980, Cancer research.

[43]  S. Ebeler,et al.  Flavonoid effects on DNA oxidation at low concentrations relevant to physiological levels. , 2008, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[44]  M. Tatematsu,et al.  Survey of various chemicals for initiating and promoting activities in a short-term in vivo system based on generation of hyperplastic liver nodules in rats. , 1983, Carcinogenesis.