Solvolysis and metabolic degradation, by rat liver, of the ultimate carcinogen, N-sulfonoxy-2-acetylaminofluorene

BA Smith, JR Springfield and HR Gutmann

The synthetic ultimate carcinogen, N-sulfonoxy-2-acetylaminofluorene (K+ salt, N-OSO3K-2-AAF), undergoes several solvolytic and metabolic reactions that have not been reported heretofore. In aqueous media, 45- 50% of N-OSO3K-2-AAF is converted to 4-hydroxy-2-acetylaminofluorene, presumably by the ionic mechanism proposed previously for the formation of the m-amidofluorenol from N-acetoxy-2-acetylaminofluorene. 4-Hydroxy- 2-acetylaminofluorene was not mutagenic and did not react with the nucleophile, guanosine. In aqueous media, rearrangement of N-OSO3K-2- AAF to the biologically inactive o-amidofluorenols, 1- and 3-hydroxy-2- acetylaminofluorene, or to the respective sulfates, were only minor reactions (approximately 3% and approximately 6-8%, respectively). In the presence of bovine serum albumin, N-OSO3K-2-AAF was converted nearly quantitatively to the sulfates of 1- and 3-hydroxy-2- acetylaminofluorene. The rearrangement was abolished by heat denaturation of the bovine serum albumin. In the presence of rat liver homogenate or of hepatic cytosol of the rat, 30-40% of N-OSO3K-2-AAF was reduced to the procarcinogen, 2-acetylaminofluorene, at the expense of 4-hydroxy-2-acetylaminofluorene. The reduction appears to be catalyzed by a low molecular weight compound in the cytosol of rat liver since denaturation of cytosolic proteins by heat had no effect on the extent of the reduction. Cytosolic reduction of N-OSO3K-2-AAF to 2- acetylaminofluorene was markedly inhibited by the nucleophile, N-acetyl- L-methionine. This observation indicates that covalent interaction of N- OSO3K-2-AAF with nucleophiles and reduction of N-OSO3K-2-AAF are competing reactions.

Volume 31, Issue 4, pp. 438-445, 04/01/1987
Copyright © 1987 by American Society for Pharmacology and Experimental Therapeutics