Use of 2-acetamidophenanthrene and 2-acetamidofluorene in investigations of mechanisms of hepatocarcinogenesis

Abstract

Comparison studies have been undertaken on the hepatocarcinogen 2-acetamidofluorene (AAF) and its nonhepatocarcinogenic analog 2-acetamidophenanthrene (AAP). Previous studies have shown that amount of compound acutely and persistently bound to rat liver DNA is comparable for the two compounds following single injections into adult Fischer rats, but that AAP fails to initiate tumors in weanling Sprague-Dawley rats. In this work we show that the amount of bound adduct from AAF and AAP is also comparable after three weeks of feeding compound to weanling Sprague-Dawley male rats. Three of the adducts found in RNA of AAP-treated rats cochromatographed on Sephadex LH-20 with two adenosine adducts and one guanosine adduct prepared by reaction of the nucleosides with N-acetoxy-N-trifluoroacetyl-2-aminophenanthrene at neutrality. Because of the lack of initiating ability of AAP in liver, we have also investigated early biochemical alterations in liver after various regimens. Feeding of either AAF or AAP to male weanling rats, followed by three weeks of DDT feeding produced no alteration in either histochemically detected gamma-glutamyltranspeptidase or in ganglioside complement in total liver homogenate. Partial hepatectomy after feeding of either AAF or AAP resulted in the appearance of new fucoganglioside and alteration in the distribution of the major gangliosides. DDT feeding after partial hepatectomy resulted in foci of elevated gamma-glutamyltranspeptidase in AAF-fed rats but not in AAP-fed rats. These results support a previous proposal that AAP may initiate tumorigenesis in rat liver, but that the promoting regimens now in use lack the ability to cause further progression of the initiated cells. The data also suggests that ganglioside synthesis may be a more sensitive marker for early stages in carcinogenesis than are the various histochemical stains now in use.