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

The hepatocarcinogen 1'-hydroxysafrole (HOS) exhibited weakinitiating activity and strong promoting activity for the inductionof enzyme-altered foci and tumors in rat liver. Thus, administrationof a single dose of HOS to rats 18 h after a 70% hepatectomy,followed by administration of phenobar-bital (PB) in the dietfor 6 months, induced a low, but statistically significant,number of foci of enzyme-altered cells. This treatment did notresult in gross liver tumors, even when the PB treatment wascontinued for 16 months. Large numbers of enzyme-altered focideveloped when HOS was administered in the diet at levels of0.05–0.25% to rats previously administered a single doseof N,N-diethylnitros-amine (DEN) 24 h after a 70% hepatectomy.Similarly, rats given a single dose of DEN 24 h after a partialhepatectomy and then fed 0.10 or 0.25% of HOS in the diet for10 months developed a high incidence of hepatocellular carcinomas.In the absence of pretreatment with DEN, dietary administrationfor at least 4 months of 0.10 or 0.25% of HOS induced significantnumbers of enzyme-altered foci; these data and liver tumor inductionby continuous feeding of HOS, in the absence of pretreatmentwith DEN, provide additional evidence for an initiating, aswell as a promoting, activity of HOS in rat liver. Concurrentadministration of the hepatic sulfotransferase inhibitor pentachlorophenolwith HOS in each of the above assays almost completely inhibitedthe initiating and promoting activities of HOS for the formationof enzyme-altered foci and tumors; these data strongly suggestthat both the initiating and promoting activities are mediatedby the sulfuric acid ester, 1'-sulfooxysafrole. HOS also exhibitedinitiating activity in adult mouse liver. Thus, dietary administrationof 0.25% of HOS for only 1 month, followed by administrationof the hepatic tumor promoter 1,4-bis2-(3,5-dichloropyridyloxy)]benzeneresulted in a high incidence and multiplicity of hepatomas by10 months. In the absence of the promoter, administration ofHOS for only 1 month induced no hepatomas; 1,4-bis2-(3,5-dichloropyridyloxy)]benzenealone induced only a low incidence. In mice not given the promoter,continuous administration of HOS