Activation Mechanism of 2-Acetylamino-9-fluorenone as a Mutagen in Salmonella typhimurium

Abstract

2-Acetylamino‰uorene (AAF) is a procarcinogen and its activation mechanisms have been investigated in detail. AAF was metabolized to 2-acetylamino-9-‰uorenone (AAF ＝O) and 2-acetylamino-9-‰uorenol by S9 mix. The mutagenicity of AAF＝O in the presence of S9 mix was equal in potency to that of AAF in Salmonella typhimurium TA1538, but the activation mechanism of AAF＝O was poorly reported. In this study, we investigated possible ultimate species derived from AAF＝O; N-hydroxy-2-acetylamino-9-‰uorenone (N-OH-AAF＝O), N-acetoxy-2-acetylamino-9-‰uorenone (N-OAc-AAF＝O), N-hydroxy-2-amino-9-‰uorenone (N-OH-AF＝O), and N-acetoxy-2-tri‰uoroacetylamino-9-‰uorenone (N-OAc-TFAAF＝O), a model compound for N-acetoxy-2-amino-9-‰uorenone (N-OAc-AF＝O), were synthesized and their mutagenicity was examined in S. typhimurium TA1538. The activation mechanism in S. typhimurium TA1538 was also investigated. The compounds in order of decreasing mutagenicity are N-OAc-TFAAF＝OÀN-OH-AF＝OÀN-OAc-AAF＝OÀ N-OH-AAF＝O. AAF＝O is at least partially responsible for the mutagenicity of AAF, since a small amount of AAF is oxidized to AAF＝O in the presence of S9 mix. Furthermore we suggest that an ultimate active species of AAF＝ O in S. typhimurium is N-OAc-AF＝O, with the same activation manner as AAF.

Activation Mechanism of N-Nitrosodialkylamines as Environmental Mutagens and Its Application to Antitumor Research

“…The chemical model activated promutagens more easily than N-nitrosodialkylamines. The experiments using diŠerent model systems allows for the improved elucidation of the mechanism(s) involved in xenobiotic metabolism (40,41).…”