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Influence of 3-Methylcholanthrene and Diet on the Binding of 2-Acetylaminofluorene and Its N-Hydroxy Metabolite to Rat Liver Nucleic Acids¹

Veterans Administration Hospital and Department of Biochemistry, University of Tennessee, Memphis, Tennessee 38104

The effect of 3-methylcholanthrene (MC), which inhibits liver carcinogenesis induced by 2-acetylaminofluorene (AAF) but not by N-hydroxy-AAF, on the binding of these hepatocarcinogens to rat liver rRNA and DNA has been studied. When MC was fed in the diet at a level of 0.005% for 1 week prior to injection of AAF-9-¹⁴C or N-hydroxy-AAF-9-¹⁴C, a 45% decrease in the binding of AAF to rRNA and DNA at 16 hr was obtained, whereas there was no decrease in the binding of N-hydroxy-AAF. These data were consistent with the hypothesis that MC inhibits AAF hepatocarcinogenesis by causing a decrease in tissue levels of N-hydroxy-AAF. The extent of persistent binding of fluorenyl metabolites to DNA 4 weeks after a single injection of AAF-9-¹⁴C and N-hydroxy-AAF-9-¹⁴C was not influenced by feeding MC in the diet. Contrary to the results obtained by feeding MC, a single i.p. injection of MC (20 mg/kg) 24 hr prior to injection of the ¹⁴C-labeled hepatocarcinogens resulted in a 40% decrease in the binding of N-hydroxy-AAF to liver rRNA and DNA; a 50% decrease in the binding of AAF-9-¹⁴C to rRNA and DNA was also obtained. The differential effect on the binding of N-hydroxy-AAF-9-¹⁴C obtained by feeding or i.p. injection of MC suggested that MC in larger doses may influence some metabolic reactions involved in the activation or deactivation of N-hydroxy-AAF. Changes in diet also had significant influence on the binding of AAF-9-¹⁴C and N-hydroxy-AAF-9-¹⁴C to rat liver rRNA and DNA. In rats fed a grain diet, there was decreased binding of these hepatocarcinogens to rRNA and increased binding to DNA compared to results obtained in rats fed a commercial laboratory diet. Ingestion of the grain diet did not affect tumorigenesis in male rats fed AAF or N-hydroxy-AAF or in female rats fed AAF but did increase the incidence and distribution of tumors in female rats fed N-hydroxy-AAF.

¹ Supported by the United States Veterans Administration and USPHS Research Grant CA-05490 from the National Cancer Institute.

Received 4/ 2/71. Accepted 5/28/71.