LIVER TUMOR-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 treat ment and the remaining animals at wk 8. At the termination relative li ver weights were significantly increased in the DEN-initiated and non- initiated groups treated with 250 ppm and 100 ppm or more, respectivel y, compared with the corresponding controls values. Light microscopica l examination showed centrilobular hepatocellular hypertrophy in all a nimals receiving 100 ppm or more. Electron microscopy also revealed ma rked increases in smooth endoplasmic reticulum in hepatocytes of the D EN 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 see n 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 is ozymes and Cx32 immunohistochemistry were already evident in the DEN p lus 250 ppm group at wk 1. The number of placental form glutathione S- transferase positive single cells was significantly increased in the D EN-initiated groups treated with 250 ppm or more. The results therefor e strongly suggest that oxfendazole exerts liver tumour promotion pote ntial. (C) 1997 Elsevier Science Ltd.