On the correlation between the hepatocarcinogenicity of the carcinogen, N-2-fluorenylacetamide, and its metabolic activation by the rat.

Abstract

The carcinogenicity of N -2-fluorenylacetamide (2-FAA) for the female Sprague-Dawley and female Fischer rats was compared. The arylamide administered i.p. induced a large number of mammary tumors in the female Sprague-Dawley rat but was not carcinogenic for the female Fischer rat. The lack of carcinogenicity of the arylamide coincided with a low capacity of the female Fischer rat for N -hydroxylation of 2-FAA to N -hydroxy-2-fluorenylacetamide. N -Hydroxy-2-fluorenylacetamide administered i.p. to the female Fischer rat yielded primarily malignant hepatic lesions. This observation provided further evidence that N -hydroxylation of 2-FAA is a requirement for the carcinogenicity of this compound. The susceptibility to hepatocarcinogenesis by N -hydroxy-2-fluorenylacetamide correlated with the extent of sulfonation of the hydroxamic acid by hepatic arylsulfotransferase in vitro and in vivo . The activity of this enzyme in the female Sprague-Dawley rat, which was refractory to hepatocarcinogenesis, was very low, whereas the arylsulfotransferase of the female Fischer rat appeared to be highly active. The evidence supports the view that hepatocarcinogenesis by 2-FAA depends on a sequential two-step mechanism of activation involving N -hydroxylation of the arylamide to an arylhydroxamic acid and sulfonation of the hydroxamic acid. Resistance to hepatocarcinogenesis in different strains of the same species appears to be due to the limited capacity to perform one of the activation steps.