Chemical Activation of Amides to Their Mutagenic and Carcinogenic Derivatives

Most amides are stable compounds, but they are convertible to extremely reactive metabolites by microsomal enzymes. The amide drugs phenacetin and acetaminophen are converted to the toxic metabolite N ‐acetyl‐ p ‐benzoquinoneimine by a combination of several cytochrome P‐450 systems. The well known hepatocarcinogen 2‐acetylaminofluorene (AAF) is metabolically activated to a highly electrophilic reactant that interacts with DNA, RNA and proteins. There are other alternative pathways which may actviate these amide compounds; nitrosation of these amides yield several directly acting mutagens, teratogens and carcinogens. We have synthesized several new N ‐nitroso compounds, namely N ‐nitrosophenacetin, N ‐nitrosoacetaminophcn and N ‐nitroso‐2‐acetylaminofluorene (NO‐AAF). The chemical structures of these compounds were characterized by spectrometric analysis of their naphthol‐coupling derivatives. The new compounds are highly mutagenic to Salmonella tester strains TA 97, TA 98, TA 100 and TA 1538 and require no microsomal metabolic activation. NO‐AAF in TA 98 is more mutagenic than MNNG and N ‐acetoxy‐AAF. The teratogenic potentials of NO‐AAF and N ‐nitrosophenacetin were studied with white Leghorn chick embryo. A high incidence of flaccid paralysis of the legs and a low incidence of feather, claw and bill malformations were found in the treated group; no such malformed embryos were found in the control group. Both N ‐nitrosophenacetin and NO‐AAF are strong electrophiles and react readily with amino acids, nucleosides, nucleic acids and proteins at neutral pH. Our data indicated that NO‐AAF is a directly acting hepatocarcinogen in Sprague‐Dawley rats. NO‐AAF seems to be a directly acting mutagen, teratogen and probably a carcinogen of new prototype.