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Activation of the Carcinogen, N-Hydroxy-2-fluorenylbenzenesulfonamide, by Desulfonylation to N-2-Fluorenylhydroxylamine in Vivo¹

Laboratory for Cancer Research, Veterans Administration Hospital, Minneapolis, Minnesota 55417 [D. M-G., H. R. G., R. E. R., Y. Y.], and the Department of Biochemistry, University of Minnesota, Minneapolis, Minnesota 55455 [D. M-G., H. R. G.]

The carcinogenicity of N-hydroxy-2-fluorenylbenzenesulfonamide (N-HO-2-FBS), a potent carcinogen for the young male and female rat by i.p. administration, was confirmed by p.o. administration of the compound to the adult male rat. The compound produced hepatic lesions that were macroscopically and microscopically very similar to those induced by N-hydroxy-2-fluorenylacetamide. Examination of the urine after the administration of N-HO-2-FBS to male and female rats revealed several metabolites indicative of desulfonylation of N-HO-2-FBS to the intermediate, N-2-fluorenylhydroxylamine. Determination of the ³⁵S:¹⁴C ratio in the tissues after i.p. injection of N-HO-2-FB-³⁵S and N-hydroxy-2-fluorenyl-9-¹⁴C-benzenesulfonamide to the female rat disclosed rapid and extensive desulfonylation of the carcinogen by the mammary gland, liver, and kidney. The mammary gland, which is the primary target of N-HO-2-FBS in the female rat, appeared to be more active in hydrolyzing the compound than the other tissues. The carcinogenicity of i.p. administered N-phenyl-2-fluorenylhydroxylamine, N-phenyl-4-biphenylylhydroxylamine, and the corresponding amines was tested in the male and female rat. N-Phenyl-2-fluorenylhydroxylamine displayed only weak activity in the female rat and was inactive in the male rat. N-Phenyl-4-biphenylylhydroxylamine was not carcinogenic either for the male or female rat. These as well as previously published data support the view that N-2-fluorenylhydroxylamine is an obligatory intermediate for the carcinogenicity of N-acyl-2-fluorenylhydroxylamines. Replacement of the hydrolyzable acyl or benzenesulfonyl group by the phenyl group results in a molecule with greatly diminished carcinogenic properties.

¹ This investigation was supported by USPHS Research Grant CA-02571 from the National Cancer Institute.

Received 11/19/70. Accepted 1/29/71.