Inhibition by pentachlorophenol of the initiating and promoting activities of 1′-hydroxysafrole for the formation of enzyme-altered foci and tumors in rat liver

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Abstract
The hepatocarcinogen 1''-hydroxysafrole (HOS) exhibited weak initiating activity and strong promoting activity for the induction of enzyme-altered foci and tumors in rat liver. Thus, administration of a single dose of HOS to rats 18 h after a 70% hepatectomy, followed by administration of phenobarbital (PB) in the diet for 6 months, induced a low, but statistically significant, number of foci of enzyme-altered cells. This treatment did not results in gross liver tumors, even when the PB treatment was continued for 16 months. Large numbers of enzyme-altered foci developed when HOS was administered in the diet at levels of 0.05-0.25% to rats previously administered a single dose of N,N-diethylnitrosamine (DEN) 24 h after a 70% hepatectomy. Similarly, rats given a single dose of DEN 24 h after a partial hepatectomy and then fed 0.10 or 0.25% of HOS in the diet for 10 months developed a high incidence of hepatocellular carcinomas. In the absence of pretreatment with DEN, dietary administration for at least 4 months of 0.10 or 0.25% of HOS induced significant numbers of enzyme-altered foci; these data and liver tumor induction by continuous feeding of HOS, in the absence of pretreatment with DEN, provide additional evidence for an initiating, as well as a promoting, activity of HOS in rat liver. Concurrent administration of the hepatic sulfotransferase inhibitor pentachlorophenol with HOS in each of the above assays almost completely inhibited the initiating and promoting activities of HOS for the formation of enzyme-altered foci and tumors; these data strongly suggest that both the initiating and promoting activities are mediated by the sulfuric acid ester, 1''-sulfooxysafrole. HOS also exhibited initiating activity in adult mouse liver. Thus, dietary administration of 0.25% of HOS for only 1 month, followed by administration of the hepatic tumor promoter 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene resulted in a high incidence and multiplicity of hepatomas by 10 months. In the absence of the promoter, administration of HOS for only 1 month induced no hepatomas; 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene alone induced only a low incidence. In mice not given the promoter, continuous administration of HOS for 3-6 months was required for hepatoma development by 16 months.

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