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The Conversion of Noncarcinogenic Aromatic Amides to Carcinogenic Arylhydroxamic Acids by Synthetic N-Hydroxylation¹

Laboratory for Cancer Research, Veterans Administration Hospital, and the Department of Biochemistry, University of Minnesota, Minneapolis, Minnesota 55417

Two essentially noncarcinogenic aromatic amides, N-2-fluorenylbenzamide and N-(7-hydroxy-2-fluorenyl)acetamide, were converted, by synthetic N-hydroxylation, to the highly carcinogenic arylhydroxamic acids, N-hydroxy-2-fluorenylbenzamide and N-hydroxy-(7-hydroxy-2-fluorenyl)acetamide, respectively. N-Hydroxy-2-fluorenylbenzamide when administered intraperitoneally gave a 100% tumor incidence in those young female rats which were alive 8 weeks after the administration of the compound. The tumor incidence in male rats was 75%. The majority of the tumors (8/11) in female rats and all of the tumors (6/6) in male rats were rapidly growing and highly invasive intraperitoneal sarcomas. In addition, female rats developed mammary adenocarcinomas. N-Benzoylphenylhydroxylamine, an analog of N-hydroxy-2-fluorenylbenzamide in which the fluorenyl moiety was replaced by the phenyl group, was not carcinogenic. These results suggest that metabolic N-hydroxylation may be a necessary, but not sufficient, condition for carcinogenesis by aromatic amides.

Metabolic studies carried out in the female rat with the use of N-hydroxy-2-fluorenylbenzamide and of N-2-fluorenylbenzamide labeled with ¹⁴C in the -carbon atom of the benzoyl group indicated that the benzoyl group of N-hydroxy-2-fluorenylbenzamide--¹⁴C was cleaved in vivo from the arylhydroxamic acid, as shown by the isolation of N-benzoyl--¹⁴C-glycine and of benzoic--¹⁴C acid from the urine. The data imply that N-2-fluorenyl-hydroxylamine, potentially a proximate agent in carcinogenesis by N-2-fluorenylacetamide and N-hydroxy-2-fluorenylacetamide, is a product of the metabolism of N-hydroxy-2-fluorenylbenzamide. Examination of rat urine or bile after the intraperitoneal administration of N-2-fluorenylbenzamide--¹⁴C disclosed only negligible amounts of N-hydroxy-2-fluorenylbenzamide. These experiments favor the view that the lack of carcinogenicity of certain aromatic amides for the rat may be explained by the inability of this species to N-hydroxylate the amide to the corresponding hydroxamic acid at a significant rate.

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

Received 1/12/67. Accepted 4/18/67.