Solvolysis and metabolic degradation, by rat liver, of the ultimate carcinogen, N-sulfonoxy-2-acetylaminofluorene.
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.
D015073:2-Acetylaminofluorene / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013056:Spectrophotometry, Ultraviolet
C047043:2-acetylaminofluorene-N-sulfate; D015073:2-Acetylaminofluorene