Specific modification of the properties of the N-hydroxylase. Relationship with carcinogenesis by aromatic amides.
N-hydroxylation represents the first and limiting step in the metabolic pathway leading to the carcinogenic activity of aromatic amines and amides. Using a method recently developed by the same authors (Analytical Biochemistry, in press), the effects of pretreatment of male adult rats with N-2-acetylaminofluorene (2AAF), N-4-acetylaminofluorene (4AAF), N-4-acetyl-aminobiphenyl, (4-AABP), and phenobarbital (PB), on the kinetic parameters of the N-hydroxylase activity have been evaluated and compared. Our resutls clearly demonstrate that both hepatocarcinogenic amides, 2-AAF and 4-AABP very significantly increase the affinity of the activating enzyme towards both substrates; on the other hand, 4-AAF and PB, which are non-carcinogenic compounds slightly decrease the affinity of the enzyme. In conclusion, the carcinogenic aromatic amides seem to specifically modify the catalytic properties of the enzyme responsible for their own metabolic activation.
D015073:2-Acetylaminofluorene / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology*; D000611:Aminobiphenyl Compounds / Q000494:pharmacology; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats
D000577:Amides; D000611:Aminobiphenyl Compounds; D002273:Carcinogens; D015073:2-Acetylaminofluorene; D006899:Mixed Function Oxygenases; D010634:Phenobarbital