Effects of various in vitro conditions on hepatic microsomal N- and C-oxygenation of aromatic amines

Abstract

The formation of reactive metabolites from carcinogenic aromatic amines in rat liver is associated with microsomal N-oxygenation. C-Oxygenation, i.e. ringhydroxylation and N-dealkylation, yields only harmless metabolites. In an attempt to elucidate the nature and origin of the reactive metabolites, the mechanism of microsomal N- and C-oxygenation of aromatic amines has been studied. Microsomal C-oxygenation of dimethylaniline shows a marked substrate optimum followed by a progressive decline; N-oxygenation of dimethylaniline and N- C-transoxygenation of dimethylaniline- Noxide show a continuous rise with increasing substrate concentration. The inhibition of C-oxygenation at high substrate concentration is not reversed by washing the microsomes. Large amounts of added N-oxygenated metabolite does not affect the C-oxygenation. Detergent treatment decreases C-oxygenation and N- C-transoxygenation but increases N-oxygenation. Electrophilic agents strongly inhibit C-oxygenation but stimulate N-oxygcnation, leaving N- C-transoxygenation unaffected. In the light of these experiments and the electron-donor properties of aromatic amines, the mechanism for C- and N-oxygenation and the release of electrophilic metabolites associated with the latter process is discussed.