The threshold dose for liver tumor promoting effects of dicyclanil in ICR mice.

To determine the threshold dose of dicyclanil (DC) that induces hepatocellular tumor-promoting effects associated with reactive oxygen species (ROS) generation via their metabolic pathways, partial hepatectomized ICR male mice were fed diets containing 0, 187.5, 375 or 750 ppm DC after an intraperitoneal injection of N-diethylnitrosamine (DEN) to initiate hepatocarcinogenesis. Immunohistochemically, the proliferating cell nuclear antigen (PCNA)-positive cell ratio was significantly increased in the DEN + 750 ppm DC group compared with the DEN alone group. However, significant increases in the number of gamma-glutamyltranspeptidase (GGT)-positive cells and formation of microsomal ROS were not observed in the DEN + DC groups compared with the DEN alone group. Real-time polymerase chain reaction (RT-PCR) showed that the expression of Cyp1a1, Cyp1a2, and OGG1genes was significantly up-regulated in mice given diets containing 375 ppm DC or more, 187.5 ppm DC or more, and 750 ppm DC, respectively. These results suggest that the threshold dose of DC that induces ROS-mediated liver tumor promotion in mice is more than 750 ppm, although expression of the Cyp1a2 gene, which is related to ROS generation, was up-regulated in the liver of mice, even at a DC dose of 187.5 ppm.

[1]  K. Mitsumori,et al.  Elevation of cell proliferation via generation of reactive oxygen species by piperonyl butoxide contributes to its liver tumor-promoting effects in mice , 2010, Archives of Toxicology.

[2]  K. Mitsumori,et al.  beta-Naphthoflavone enhances oxidative stress responses and the induction of preneoplastic lesions in a diethylnitrosamine-initiated hepatocarcinogenesis model in partially hepatectomized rats. , 2008, Toxicology.

[3]  P. Lin,et al.  2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces oxidative stress, DNA strand breaks, and poly(ADP-ribose) polymerase-1 activation in human breast carcinoma cell lines. , 2007, Toxicology letters.

[4]  K. Mitsumori,et al.  Reactive Oxygen Species Are Possibly Involved in the Mechanism of Flumequine-Induced Hepatocarcinogenesis in Mice , 2007 .

[5]  Meilan Jin,et al.  Gene Expression Analysis on the Dicyclanil-Induced Hepatocellular Tumors in Mice , 2006, Toxicologic pathology.

[6]  K. Mitsumori,et al.  Possible involvement of oxidative stress in dicyclanil-induced hepatocarcinogenesis in mice , 2006, Archives of Toxicology.

[7]  C. Kahler-Venter,et al.  Hepatocellular carcinoma caused by iron overload: a possible mechanism of direct hepatocarcinogenicity. , 2006, Toxicology.

[8]  N. Machida,et al.  Molecular pathological analysis on the mechanism of liver carcinogenesis in dicyclanil-treated mice. , 2005, Toxicology.

[9]  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.

[10]  S. Fukushima,et al.  Formation of 8-hydroxydeoxyguanosine and cell-cycle arrest in the rat liver via generation of oxidative stress by phenobarbital: association with expression profiles of p21(WAF1/Cip1), cyclin D1 and Ogg1. , 2002, Carcinogenesis.

[11]  L. Valgimigli,et al.  Measurement of oxidative stress by EPR radical-probe technique. , 2001, Free radical biology & medicine.

[12]  G. Robino,et al.  Oxidative stress-related molecules and liver fibrosis. , 2001, Journal of hepatology.

[13]  K. Koike,et al.  Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. , 2001, Cancer research.

[14]  W. Backes,et al.  Ethylbenzene induces microsomal oxygen free radical generation: antibody-directed characterization of the responsible cytochrome P450 enzymes. , 2000, Toxicology and applied pharmacology.

[15]  J. Stegeman,et al.  Oxidative inactivation of cytochrome P-450 1A (CYP1A) stimulated by 3,3',4,4'-tetrachlorobiphenyl: production of reactive oxygen by vertebrate CYP1As. , 1999, Molecular pharmacology.

[16]  D. Nakae,et al.  Hepatotoxicity and consequently increased cell proliferation are associated with flumequine hepatocarcinogenesis in mice. , 1999, Cancer letters.

[17]  A. Cederbaum,et al.  Production of reactive oxygen species by microsomes enriched in specific human cytochrome P450 enzymes. , 1998, Free radical biology & medicine.

[18]  H. Kasai,et al.  Analysis of a form of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis. , 1997, Mutation research.

[19]  Y. Konishi,et al.  Involvement of 8-hydroxyguanine formation in the initiation of rat liver carcinogenesis by low dose levels of N-nitrosodiethylamine. , 1997, Cancer research.

[20]  G. Cantelli-forti,et al.  Paramagnetic resonance in detecting carcinogenic risk from cytochrome P450 overexpression. , 1996, Journal of investigative medicine : the official publication of the American Federation for Clinical Research.

[21]  T. Shimada,et al.  Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes. , 1991, Chemical research in toxicology.

[22]  A. Grollman,et al.  Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG , 1991, Nature.

[23]  M. Mckee,et al.  Organometal-induced increases in oxygen reactive species: the potential of 2',7'-dichlorofluorescin diacetate as an index of neurotoxic damage. , 1990, Toxicology and applied pharmacology.

[24]  G. -. Lee,et al.  Comparative study of diethylnitrosamine-initiated two-stage hepatocarcinogenesis in C3H, C57BL and BALB mice promoted by various hepatopromoters. , 1989, Carcinogenesis.

[25]  T. Dragani,et al.  Two-Stage Liver Carcinogenesis in the Mouse , 1987, Toxicologic pathology.

[26]  D. Bass,et al.  Flow cytometric quantitation of oxidative product formation by polymorphonuclear leukocytes during phagocytosis. , 1984, Journal of immunology.

[27]  A. Seligman,et al.  HISTOCHEMICAL AND ULTRASTRUCTURAL DEMONSTRATION OF γ-GLUTAMYL TRANSPEPTIDASE ACTIVITY , 1969 .

[28]  A. Federico,et al.  Oxidative stress in viral and alcoholic hepatitis. , 2003, Free radical biology & medicine.

[29]  B. Halliwell,et al.  Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. , 1996, The Biochemical journal.

[30]  T. Kensler,et al.  An overview of the relationship between oxidative stress and chemical carcinogenesis. , 1991, Free radical biology & medicine.