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On the Mechanism of Protein Binding of N-2-Fluorenylacet amide. The Deacetylation of N-(1-Hydroxy-2-fluorenyl)-acetamide and the Effect of Ethionine^*

( Radioisotope Service, Veterans Administration Hospital, and the Department of Physiological Chemistry, University of Minnesota, Minneapolis, Minn.)

Homogenates of six rat tissues metabolized the o-amidofluorenol, N-(1-hydroxy-2-fluorenyl)acetamide, as judged by the disappearance of the phenolic hydroxyl group of the compound from the incubation systems. By the same criterion, N-(7-hydroxy-2-fluorenyl)acetamide was resistant to metabolic attack.

The deacylation of N-(1-hydroxy-2-fluorenyl)acetamide, N-(7-hydroxy-2-fluorenyl)acetamide, N-2-fluorenylbutyramide, and N-2-fluorenylacetamide by twelve rat tissues was examined with the use of spectrophotometric technics and radioactive tracer methods. Only N-(1-hydroxy-2-fluorenyl)acetamide was deacetylated by all tissues.

The action of 0.1 M potassium fluoride upon deacetylation of N-(1-hydroxy-2-fluorenyl)acetamide-1-C¹⁴ and upon protein labeling by the radioactivity of N-2-fluorenylacetamide-9-C¹⁴ was examined in rat liver homogenates; 0.1 M potassium fluoride inhibited deacetylation as well as protein labeling. It was confirmed in separate experiments that fluoride under these conditions enhanced hydroxylation as previously described.

The data support a mechanism of protein binding of the carcinogen previously suggested on the basis of in vitro evidence. This mechanism involves o-hydroxylation of N-2-fluorenylacetamide followed by deacetylation and subsequent oxidation of the resulting o-aminophenol to the o-quinoneimine which in turn may combine with protein.

The role of the inhibition of protein synthesis by DL-ethionine upon the binding of N-2-fluorenylacetamide-9-C¹⁴ was tested. No effect of this antimetabolite upon binding was observed.

^* This investigation was supported by grants from the National Cancer Institute, U.S. Public Health Service (C-2571), and the Minnesota Division of the American Cancer Society, and presented in part at the 50th annual meeting of the American Association for Cancer Research, Atlantic City, N.J. April, 1959.

Received 1/21/60.