Interaction of the synthetic ultimate carcinogens, N-sulfonoxy- and N-acetoxy-2-acetylaminofluorene, and of enzymatically activated N-hydroxy-2-acetylaminofluorene with nucleophiles.
The interaction of four cellular nucleophiles with the putative ultimate carcinogens N-sulfonoxy-2-[ring-3H]acetylaminofluorene (N-sulfonoxy-2-AAF) and N-acetoxy-2-[ring-3H] acetylaminofluorene (N-acetoxy-2-AAF), and with N-hydroxy-2-[ring-3H]acetylaminofluorene (N-hydroxy-2-AAF) activated to the ultimate carcinogens by enzymatic sulfonation or transacetylation was determined. The adducts were isolated and adduct formation was quantified by isotope dilution. The order of nucleophilicity of the acceptors was guanosine greater than tRNA congruent to polyguanylic acid (poly G) greater than N-acetyl-L-methionine when N-sulfonoxy-2-AAF, N-acetoxy-2-AAF or N-hydroxy-2-AAF activated by transacetylation were the electrophiles. In the case of N-hydroxy-2-AAF activated by enzymatic sulfonation, the order of nucleophilicity was N-acetyl-L-methionine greater than guanosine congruent to tRNA greater than poly G. The increase in the reactivity of N-acetyl-L-methionine is hypothesized to be due to cytosolic enzyme(s) which facilitate transfer of the methionine residue from the nitrogen to carbon atoms 3 and 1 of the fluorene moiety. Of the two synthetic esters, N-sulfonoxy-2- AAF exhibited greater electrophilicity than N-acetoxy-2-AAF. The rate of adduct formation of N-sulfonoxy-2-AAF and of N-acetoxy-2-AAF with each nucleophile was a function of nucleophile concentration, indicative of a bimolecular reaction mechanism. The interaction is thought to involve attack of the nucleophile on the uncharged ultimate carcinogen, although interaction with an ion pair cannot be eliminated. The mutagenicity of N-sulfonoxy-2-AAF, N-acetoxy-2-AAF and of enzymatically activated N-hydroxy-2-AAF was evaluated by the Ames test. N-Sulfonoxy-2-AAF was virtually inactive, while N-acetoxy-2-AAF exhibited weak mutagenicity. N-Hydroxy-2-AAF activated by enzymatic sulfonation exhibited greater mutagenicity than synthetic N-sulfonoxy-2-AAF. The mutagenicity and reactivity of ultimate carcinogens derived from N-hydroxy-2-AAF by enzymatic activation do not necessarily coincide with the mutagenicity and reactivity of the synthetic ultimate carcinogens.
D015073:2-Acetylaminofluorene / Q000031:analogs & derivatives* / Q000494:pharmacology; D000099:Acetoxyacetylaminofluorene / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D055598:Chemical Phenomena; D002621:Chemistry; D006151:Guanosine; D006881:Hydroxyacetylaminofluorene / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives; D009152:Mutagenicity Tests; D009154:Mutation / Q000187:drug effects; D011068:Poly G; D012343:RNA, Transfer; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects
D006151:Guanosine; C047043:2-acetylaminofluorene-N-sulfate; D011068:Poly G; D006881:Hydroxyacetylaminofluorene; D000099:Acetoxyacetylaminofluorene; D012343:RNA, Transfer; C006379:N-acetylmethionine; D015073:2-Acetylaminofluorene; D008715:Methionine