title: Microsomal N-oxidation of the hepatocarcinogen N-methyl-4-aminoazobenzene and the reactivity of N-hydroxy-N-methyl-4-aminoazobenzene.
abstract: The N-oxidation of the hepatocarcinogen N-methyl-4-aminoazobenzene (MAB) was catalyzed by hepatic microsomes in a reduced pyridine nucleotide- and oxygen-dependent reaction. The initial N-oxidation product, N-hydroxy-N-methyl-4-aminoazobenzene (N-HO-MAB), was readily oxidized to a second product that yielded N-hydroxy-4-aminoazobenzene upon subsequent acid treatment. The secondary N-oxidation product may be formed nonenzymatically and is presumed to be N-HO-MAB N-oxide or its dehydrated derivative, N-(p-phenylazophenyl)nitrone. Under the same conditions, MAB was also oxidatively N-dealkylated to 4-aminoazobenzene, which was N-oxidized to N-hydroxy-4-aminoazobenzene. Unlike the latter reactions, the microsomal N-oxidation of MAB was independent of cytochrome P-450, as shown by its lack of sensitivity to inhibition by 2-[(2,4-dichloro-6-phenyl)phenoxy]ethylamine and its inability to utilize cumene hydroperoxide in place of reduced pyridine nucleotides and oxygen. The N-oxidation of MAB was also catalyzed by the purified microsomal flavoprotein mixed-function amine oxidase of Ziegler et al. The noncarcinogenic dye N-ethyl-4-aminoazobenzene was metabolized similarly to MAB. For male animals the hepatic levels of MAB N-oxidase activity were in the order: rat greater than hamster, guinea pig greater than mouse, rabbit. Little or no MAB N-oxidase activity was present in several extrahepatic rat tissues. N-HO-MAB, N-hydroxy-N-ethyl-4-aminoazobenzene, and N-hydroxy-4-aminoazobenzene catalyzed the aerobic oxidation of cysteine and glutathione. These hydroxylamines also bound covalently to proteins. The binding of N-HO-MAB with nucleic acids was only 3 to 6% that observed with serum albumin. Under anhydrous conditions the nitrone generated aerobically from N-HO-MAB reacted with carbon-carbon or carbon-nitrogen double bonds, or both, in fatty acids, retinol, purines, and pyrimidines to yield isoxazolidine and/or oxadiazolidine addition products. The nitrone from N-hydroxy-N-ethyl-4-aminoazobenzene was much less reactive under these conditions. Syntheses of N-HO-MAB and N-hydroxy-N-ethyl-4-aminoazobenzene are reported.
mesh_terms: D062365:Aminobenzoates; D000818:Animals; D001391:Azo Compounds / Q000378:metabolism*; D006224:Cricetinae; D003545:Cysteine / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010084:Oxidation-Reduction; D011506:Proteins / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D012709:Serum Albumin / Q000378:metabolism; D013045:Species Specificity; D010128:p-Aminoazobenzene / Q000031:analogs & derivatives / Q000378:metabolism*; D004124:p-Dimethylaminoazobenzene / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D062365:Aminobenzoates; D001391:Azo Compounds; D011506:Proteins; D012709:Serum Albumin; C010738:N-hydroxy-4-(methylamino)azobenzene; D010128:p-Aminoazobenzene; C005202:N-methyl-4-aminoazobenzene; D012313:RNA; D004247:DNA; D004124:p-Dimethylaminoazobenzene; D006899:Mixed Function Oxygenases; D005978:Glutathione; D003545:Cysteine