Liver tumour-promoting effects of oxfendazole in rats.
To examine whether oxfendazole has tumour-promoting activity, a total of 100 male Fisher 344 rats were initiated with a single ip injection of 100 mg/kg of diethylnitrosamine (DEN) or given saline vehicle alone and starting 1 wk later given diet containing 500, 250, 100, 10 or 0 ppm of oxfendazole for 8 wk. Sub-groups of five rats each from the DEN plus 250 and 0 ppm groups were killed after wk 1 of oxfendazole treatment and the remaining animals at wk 8. At the termination relative liver weights were significantly increased in the DEN-initiated and non-initiated groups treated with 250 ppm and 100 ppm or more, respectively, compared with the corresponding controls values. Light microscopical examination showed centrilobular hepatocellular hypertrophy in all animals receiving 100 ppm or more. Electron microscopy also revealed marked increases in smooth endoplasmic reticulum in hepatocytes of the DEN plus 500 ppm group. Furthermore, induction of cytochrome P-450 (CYP) 1A1/2, 2B1/2 or 4A1 was observed in the DEN plus 100 ppm group, that of CYP 1A1/2 being most marked. A similar change in CYP 1A1/2 was seen in the DEN plus 10 ppm group. The numbers and areas of connexin 32 (Cx32)-positive spots per hepatocyte were also significantly decreased in a dose-dependent manner. Similar changes in liver weights, P-450 isozymes and Cx32 immunohistochemistry were already evident in the DEN plus 250 ppm group at wk 1. The number of placental form glutathione S-transferase positive single cells was significantly increased in the DEN-initiated groups treated with 250 ppm or more. The results therefore strongly suggest that oxfendazole exerts liver tumour promotion potential.
Mitsumori
K
K
Division of Pathology, National Institute of Health Sciences, Tokyo, Japan.
Onodera
H
H
Shoda
T
T
Uneyama
C
C
Imazawa
T
T
Takegawa
K
K
Yasuhara
K
K
Watanabe
T
T
Takahashi
M
M
D000284:Administration, Oral; D000818:Animals; D000871:Anthelmintics / Q000633:toxicity*; D001562:Benzimidazoles / Q000633:toxicity*; D002273:Carcinogens; D002452:Cell Count; D003043:Cocarcinogenesis; D017630:Connexins / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004052:Diethylnitrosamine; D004790:Enzyme Induction / Q000187:drug effects; D005982:Glutathione Transferase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D008297:Male; D015388:Organelles / Q000187:drug effects / Q000648:ultrastructure; D051381:Rats; D011916:Rats, Inbred F344; D000097002:Gap Junction beta-1 Protein
D000871:Anthelmintics; D001562:Benzimidazoles; D002273:Carcinogens; D017630:Connexins; D003577:Cytochrome P-450 Enzyme System; D004052:Diethylnitrosamine; D005982:Glutathione Transferase; D000097002:Gap Junction beta-1 Protein; C011030:oxfendazole