|
Sign In to gain access to subscriptions and/or personal tools.
|
Liver Tumor Promoting Effects of Fenbendazole in Rats
Toshiyuki Shoda
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
Hiroshi Onodera
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
Makio Takeda
Toxicology Division, Institute of Environmental Toxicology, Uchimoriya-cho 4321, Mitsukaido-shi, Ibaraki 303-0043, Japan
Chikako Uneyama
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
Takayoshi Imazawa
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
Kiyoshi Takegawa
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
Kazuo Yasuhara
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
Tomoyuki Watanabe
Research and Development Division, Sumika Technoservice Corporation, 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-8558, Japan
Masao Hirose
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
Kunitoshi Mitsumori
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
In order to examine whether fenbendazole has tumor-promoting activity, a total of 70 male Fischer 344 rats were initiated with a single intraperitoneal injection of 100 mg/kg of diethylnitrosamine (DEN) or were given the saline vehicle alone; beginning 1 wk later, rats were given a diet containing 3,600; 1,800; 600; 200; 70; or 0 ppm of fenbendazole for 8 wk. Subgroups of 5 rats each from the DEN+1,800; DEN+0; 1,800; and 0 ppm groups were euthanatized after 1 wk of fenbendazole treatment, and the remaining animals were euthanatized at 8 wk. After 1 wk, relative liver weights (ratios to body weights) were significantly increased in the DEN+1,800 and 1,800 ppm groups, and based on light microscopy, periportal hepatocellular hypertrophy was evident in these groups. After 8 wk, relative liver weights were significantly increased in the groups given  600 ppm with or without DEN initiation. Periportal hepatocellular hypertrophy, characterized by a marked increase in smooth endoplasmic reticulum, was observed in the groups given 600 ppm with or without DEN initiation. Induction of cytochrome P-450 (CYP) 1A2, 2B1, or 4A1 was noted in the fenbendazole-treated groups with or without DEN initiation; that associated with CYP 1A2 was most marked. Positive immunostaining for anti-CYP 1A1/2 or CYP 2B1/2 was observed diffusely in the livers of animals in the DEN+1,800 and DEN+3,600 ppm groups. The numbers and areas of connexin 32 (Cx32)-positive spots per square centimeter in centrilobular hepatocytes were significantly decreased in an almost dose-dependent manner with fenbendazole treatment after DEN initiation. In situ hybridization for Cx32 mRNA revealed a remarkable decrease in its expression in the centrilobular hepatocytes in the DEN+70 ppm group. The numbers of glutathione S-transferase placental-form positive single cells (plus mini foci) were significantly increased in the DEN+1,800 and DEN+3,600 ppm groups. Since those agents that induce CYP 2B1/2 isozymes and reduce Cx32 in centrilobular hepatocytes have been suggested to be liver tumor promoters, the present results indicate that fenbendazole may be a liver tumor promoter.
Key Words: Connexin • carcinogenesis • promotion • cytochrome P-450 • benzimidazole
References
- Dalvi RR (1989). Comparative studies on the effect of fenbendazole on the liver and liver microsomal enzymes in goats, quail and rats. Vet. Res. Commun. 13: 135-139.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Dalvi RR, Gawai KR, and Dalvi PS (1991). Lack of in vivo and in vitro effects of fenbendazole on phase I and phase II biotransformation enzymes in rats, mice and chickens. Vet. Hum. Toxicol. 33: 548-551.[Web of Science][Medline]
[Order article via Infotrieve]
- Diwan BA, Rice JM, Nims RW, Lubet RA, Hu H., and Ward JM (1988). P450 enzyme induction by 5-ethyl-5-phenylhydantoin and 5,5-diethylhydantoin, analogues of barbiturate tumor promoters phenobarbital and barbital, and promotion of liver and thyroid carcinogenesis initiated by N-nitrosodiethylamine in rats. Cancer Res. 48: 2492-2497.[Abstract/Free Full Text]
- Diwan BA, Rice JM, Ohshima M., Ward JR, and Dove LF (1985). Comparative tumor-promoting activities of phenobarbital, amobarbital, barbital sodium and barbituric acid on livers and other organs of male F344/NCr rats following initiation with N-nitrosodiethylamine. J. Natl. Cancer Inst. 74: 509-515.[Web of Science][Medline]
[Order article via Infotrieve]
- Fujisawa H., Takeda M., Yoshida T., and Chiba Y. (1996). In situ hybridization technique using digoxygenin-labeled cRNA probe for rat Cx32 mRNA. Jpn. J. Histotechnol. 5: 13-18.
- Gleizes C., Eeckhoutte C., Pineau T., Alvinerie M. and Galtier P. (1991). Inducing effect of oxfendazole on cytochrome P4501A2 in rabbit liver. Biochem. Phannacol. 41: 1813-1820.[CrossRef]
- Hertzberg EL (1984). A detergent-independent procedure for the isolation of gap junctions from rat liver. J. Biol. Chem. 259: 9936-9943.[Abstract/Free Full Text]
- Isogai M., Shimada N., Kamataki T., Imaoka S., and Funae Y. (1993). Changes in the amount of cytochrome P450 in rat hepatic microsomes produced by cyclosporin A. Xenobiotica 23: 799-807.[Web of Science][Medline]
[Order article via Infotrieve]
- Ito N., Hasegawa R., Imaida K., Hirose M., and Shirai T. (1996). Medium-term liver and multi-organ carcinogenesis bioassays for carcinogens and chemopreventive agents. Exp. Toxicol. Pathol. 48: 113-119.
- Klaunig JE and Ruch RJ (1990). Role of inhibition of intercellular communication in carcinogenesis. Lab. Invest. 62: 135-146.[Web of Science][Medline]
[Order article via Infotrieve]
- Krutovskikh VA, Mesnil M., Mazzoleni G., and Yamasaki H. (1995). Inhibition of rat liver gap junction intercellular communication by tumor-promoting agents in vivo. Lab. Invest. 72: 571-577.[Web of Science][Medline]
[Order article via Infotrieve]
- Laemmli UK (1970). Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680-685.[CrossRef][Medline]
[Order article via Infotrieve]
- Lubet RA, Nims RW, Ward JM, Rice JM, and Diwan BA (1989). Induction of cytochrome P450b and its relationship to liver tumor promotion. J. Am. Coll. Toxicol. 8: 259-268.[CrossRef]
- Mesnil M., Piccoli C., and Yamasaki H. (1993). An improved long-term culture of rat hepatocytes to detect liver tumor-promoting agents: Results with phenobarbital. Eur. J. Pharmacol. Environ. Toxicol. Pharmacol. Sect. 248: 59-66.[Web of Science][Medline]
[Order article via Infotrieve]
- Mitsumori K., Onodera H., Shoda T., Uneyama C., Imazawa T., Takegawa K., Yasuhara K., Watanabe T., and Takahashi M. (1997). Liver tumor-promoting effects of oxfendazole in rats. Food Chem. Toxicol. 35: 799-806.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Neveu MJ, Babcock KL, Hertzberg EL, Paul DL, Nicholson BJ, and Pitot HC (1994). Colocalized alterations in connexin 32 and cytochrome P450IIB1/2 by phenobarbital and related liver tumor promoters. Cancer Res. 54: 3145-3152.[Abstract/Free Full Text]
- Neveu MJ, Hully JR, Babcock KL, Hertzberg EL, Nicholson BJ, Paul DL, and Pitot HC (1994). Multiple mechanisms are responsible for altered expression of gap junction genes during oncogenesis in rat liver. J. Cell Sci. 107: 83-95.[Abstract]
- Neveu MJ, Hully JR, Paul DL, and Pitot HC (1990). Reversible alteration in the expression of the gap junctional protein connexin 32 during tumor promotion in rat liver and its role during cell proliferation. Cancer Commun. 2: 21-31.[Web of Science][Medline]
[Order article via Infotrieve]
- Peraino C., Fry Rjm, Staffeldt E., and Christopher JP (1975). Comparative enhancing effects of phenobarbital, amobarbital, diphenylhydantoin and dichlorodiphenyltrichloroethane on 2-acetylaminofluorene-induced hepatic tumorigenesis in the rat. Cancer Res. 35: 2884-2890.[Abstract/Free Full Text]
- Sato K. (1988). Glutathione S-transferase and hepatocarcinogenesis. Jpn. J. Cancer Res. (Gann) 79: 556-572.
- Shinozuka H., Lombardi B., and Abanobi SE (1982). A comparative study of the efficacy of four barbiturates as promoters of the development of
 -glutamyltranspeptidase-positive foci in the liver of carcinogen treated rats. Carcinogenesis 3: 1017-1020.[Abstract/Free Full Text] - Takeda A., Kanoh M., Shimazu T., and Takeuchi N. (1988). Monoclonal antibodies recognizing different epitopes of the 27-kDa gap junction protein in rat liver. J. Biochem. 104: 901-907.[Abstract/Free Full Text]
- World Health Organization ( 1991). WHO Food Additive Series, No. 29. Toxicological Evaluation of Certain Veterinary Drug Residues in Food: Thirty-Eighth Meeting of the Joint FAO/WHO Expert Committee on Food Additives. World Health Organization, Geneva, pp. 45-77.
- World Health Organization ( 1996). WHO Technical Report Series, No. 864. Evaluation of Certain Veterinary Drug Residues in Food: Forty-Fifth Report of the Joint FAO/WHO Expert Committee on Food Additives. World Health Organization, Geneva, pp. 21-26.
Toxicologic Pathology, Vol. 27, No. 5,
553-562 (1999)
DOI: 10.1177/019262339902700509
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter What's this?
This article has been cited by other articles:
|
|
|
|
 
M. Takahashi, M. Shibutani, G.-H. Woo, K. Inoue, H. Fujimoto, K. Igarashi, J. Kanno, M. Hirose, and A. Nishikawa
Cellular distributions of molecules with altered expression specific to the tumor promotion process from the early stage in a rat two-stage hepatocarcinogenesis model
Carcinogenesis,
November 1, 2008;
29(11):
2218 - 2226.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Shoda, K. Mitsumori, H. Onodera, K. Toyoda, C. Uneyama, K. Takada, and M. Hirose
Live Tumor-Promoting Effect of {beta}-Naphthoflavone, a Strong CYP 1A1/2 Inducer, and the Relationship between CYP 1A1/2 Induction and Cx32 Decrease in Its Hepatocarcinogenesis in the Rat
Toxicol Pathol,
July 1, 2000;
28(4):
540 - 547.
[Abstract]
[PDF]
|
|
|
|
|
