ALTERATION OF METABOLISM OF CARCINOGEN N-2-FLUORENYLACETAMIDE BY ACETANILIDE

In order to elucidate the mechanisms underlying the reduction of the toxicity and carcinogenicity of N-2-fluorenylacetamide by the simultaneous administration of acetanilide, the fate of the carcinogen under these conditions was investigated. In vitro experiments showed that nitrosobenzene, but not chloramphenicol, inhibited the binding of 2-nitrosofluorene to serum albumin. Acute experiments in male rats in which 250 and 500 μmoles of acetanilide were injected 2 hours prior to 10.4 μmoles of 14C-labeled N-2-fluorenylacetamide yielded no significant difference in the urinary and tissue metabolites of the carcinogen. However, 4 groups of rats pretreated for 6 weeks with 0.02% N-2-fluorenylacetamide, or with 0.02% carcinogen plus 0.8% acetanilide, or with 0.8% acetanilide, or controls, then injected with a dose of tagged carcinogen, yielded appreciable differences in these parameters. Radio-activity in liver and plasma, and isotope bound to liver proteins as well as in the subcellular fractions of liver, showed the lowest binding in rats pretreated with unlabeled carcinogen. Rats fed acetanilide alone or acetanilide plus carcinogen had similar somewhat depressed binding, 65-70% of that of untreated controls. Radioactivity was also firmly bound to deoxyribonucleic acid in the same relative pattern in the 4 groups. As compared to controls, animals pretreated with N-2-fluorenylacet-amide excreted more radioactivity from the dose of labeled agent. The glucosiduronic fraction was higher, and in particular the active carcinogenic intermediate N-hydroxy-N-2-fluorenylacetamide, as glucuronide, amounted to 4.3% of dose compared to 0.21% in controls. Prefeeding of acetanilide, or acetanilide plus carcinogen gave a pattern of urinary carcinogen metabolites similar to that in controls. In particular the important N-hydroxy derivative increased only slightly in the 6-week feeding period. Thus, the reduction in toxicity and carcinogenicity of N-2-fluorenyl-acetamide by the simultaneous administration of acetanilide can be traced to the lower levels of active N-hydroxy metabolite and possibly also to decreased amounts of active carcinogen bound to cellular and molecular receptors. © 1968.