Shigetsugu Wada

Modulatory interaction between initial clofibrate treatment and subsequent administration of 2-acetylaminofluorene or sodium phenobarbital on glutathione S-transferase positive lesion development

The effects of 2-acetylaminofluorene (2-AFF) or sodium phenobarbital (PB) treatment subsequent to clofibrate (CF) administration in terms of preneoplastic lesion development and induction of hepatocellular carcinomas (HCC) were studied using Fischer 344 rats. Animals received CF (0.3% in diet) for the initial 30 weeks, and then either 2-AAF (0.01% in diet), PB (0.05% in diet) or basal diet until week 78. Further groups were initially given basal diet, and then treated with 2-AAF or PB week 30. Two-thirds partial hepatectomy was carried out on all animals at week 3, sacrifice of representative groups being performed at weeks 30, 48 and 78. No glutathione S-transferase placental form positive (GST-P+) or negative focal or nodular lesions were apparent at the cessation of CF administration. The induction of GST-P+ focal lesions by 2-AAF was markedly decreased at week 48 in the group previously given CF (P less than 0.05) and furthermore, the respective incidences of HCC at week 78 were 4/17 (23.5%) in the CF----2-AAF group and 7/17 (41.2%) in the 2-AAF alone case. No significant differences between CF----PB and PB alone groups were evident with regard to either GST-P+ lesions and HCC at weeks 48 and 78. No CF-specific GST-P negative neoplastic nodules or HCC were observed in any of the experimental groups. These results suggest that pretreatment with CF may inhibit the induction of GST-P+ focal lesions and HCC by subsequently administrated 2-AAF and that CF demonstrates no initiating activity for liver carcinogenesis under the present condition.

Modifying Influence of Swine Serum-induced Liver Fibrosis on Development of Preneoplastic Lesions in Rat Liver

Modifying effects of fibrosis or a cirrhotic state, caused by treatment with swine serum (SS), on the induction of preneoplastic focal lesions were assessed in a rat medium‐term liver bioassay model for the detection of environmental carcinogens, in which the test compound is administered during the promotion phase after initiation with diethylnitrosamine. In experiment I, repeated intraperitoneal administration of SS concomitantly with the hepatopromoting agent deoxycholic acid (DCA) or phenobarbital (PB) resulted in a cirrhotic state and a significant increase in the number or size of preneoplastic glutathione S‐transferase placental form (GST‐P)‐positive liver cell foci as compared to the corresponding DCA or PB alone groups. In experiment II, SS was given prior to commencement of tbe same medium‐term bioassay system, in which a known hepatopromoting agent, DCA, 17‐α‐ethynylestradiol, or 2‐acetyIaminofluorene, was applied. In this case, the liver did not show obvious cirrhotic change and, rather than any enhancement, slight inhibition of promotion occurred. The results indicate that a coexisting, but not a pre‐existing, cirrhotic condition acts to increase growth pressure on GST‐P+ preneoplastic foci, and suggest that concomitant administration of SS with the promoting agent could be applied to improve the sensitivity of the assay protocol.