Liver tumor promoting effects of fenbendazole in rats.
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 > or =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 > or =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.
Shoda
T
T
Division of Pathology, National Institute of Health Sciences, Tokyo, Japan.
Onodera
H
H
Takeda
M
M
Uneyama
C
C
Imazawa
T
T
Takegawa
K
K
Yasuhara
K
K
Watanabe
T
T
Hirose
M
M
Mitsumori
K
K
D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D000969:Antinematodal Agents / Q000633:toxicity*; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D015197:Carcinogenicity Tests; D003043:Cocarcinogenesis; D017630:Connexins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004052:Diethylnitrosamine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005273:Fenbendazole / Q000378:metabolism / Q000633:toxicity*; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007274:Injections, Intraperitoneal; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D000097002:Gap Junction beta-1 Protein
D000477:Alkylating Agents; D000969:Antinematodal Agents; D017630:Connexins; D003577:Cytochrome P-450 Enzyme System; D004052:Diethylnitrosamine; D005273:Fenbendazole; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007527:Isoenzymes; D012333:RNA, Messenger; D000097002:Gap Junction beta-1 Protein; C496558:Gstp1 protein, rat