Oxidative transformation of 2-acetylaminofluorene by a chemical model for cytochrome P450: A water-insoluble porphyrin and tert-butyl hydroperoxide.
Oxidation of 2-acetylaminofluorene (AAF), a carcinogen, by a chemical model for cytochrome P450 was investigated to identify an active mutagen and elucidate the oxidation pathway. The oxidation system consisted of a water-insoluble tetrakis(pentafluorophenyl)porphyrinatoiron(III) chloride and tert-butyl hydroperoxide. The mutagen derived from AAF by the chemical model was 2-nitro-9-fluorenone (NO(2)=FO), which was mutagenic in Salmonella typhimurium TA1538. AAF was oxidized initially at position 9 of the fluorene carbon by the chemical model forming 2-acetylamino-9-fluorenol (AAF-OH), and then oxidized further to 2-acetylamino-9-fluorenone (AAF=O) as a major product. Initial oxidation of the nitrogen formed 2-nitrofluorene (NO(2)F), and further oxidation yielded 2-nitro-9-fluorenol (NO(2)F-OH) as a minor product. These products, AAF-OH, AAF=O, NO(2)F, and NO(2)F-OH, and their presumable common intermediate, N-hydroxy-2-acetylaminofluorene, were oxidized by the chemical model, and the formation of NO(2)F=O was determined. These results showed that NO(2)F=O was the mutagen derived from AAF in the presence of the chemical model and was formed via oxidation of N-OH-AAF, NO(2)F, and NO(2)F-OH. These results may lead to a new metabolic pathway of AAF.
Inami
Keiko
K
Kyoritsu University of Pharmacy, Shibakoen 1-5-30, Minato-ku, Tokyo 105-8512, Japan. inami-kk@kyoritsu-ph.ac.jp
Mochizuki
Masataka
M
D015073:2-Acetylaminofluorene / Q000737:chemistry*; D002273:Carcinogens / Q000737:chemistry*; D003577:Cytochrome P-450 Enzyme System; D008956:Models, Chemical; D009152:Mutagenicity Tests; D010084:Oxidation-Reduction; D011166:Porphyrins / Q000737:chemistry*; D012486:Salmonella typhimurium / Q000187:drug effects; D014867:Water; D020122:tert-Butylhydroperoxide / Q000737:chemistry*
D002273:Carcinogens; D011166:Porphyrins; D014867:Water; D003577:Cytochrome P-450 Enzyme System; D020122:tert-Butylhydroperoxide; D015073:2-Acetylaminofluorene