Relationship of metabolic activation of N-hydroxy-N-acylarylamines to biological response in the liver and mammary gland of the female CD rat.

Intraperitoneal injection of the N-formyl, N-acetyl, or N-propionyl derivatives of N-hydroxy-4-aminobiphenyl, N-hydroxy-2-acetylaminofluorene, or N-(4-biphenyl)glycolamide disclosed that the ability of these compounds to induce mammary tumors in the female CD rat was greater if the compound was able to be metabolized to a reactive product by one of two soluble enzymes obtained from both the liver and mammary gland. A similar but weaker association between the formation of gamma-glutamyltranspeptidase-positive foci and cellular altered foci of the liver was also observed. The enzyme related to the tumorigenicity of these compounds was characterized by a highly specific capacity to form adducts from the acetyl and propionyl derivatives. The other enzyme exhibited greater activity with N-formyl substrates. The two enzyme activities were separable by ion-exchange chromatography on DEAE-cellulose and by gel filtration on Sephacryl. Liver microsomes also possessed the capacity to activate both the formyl and acetyl derivatives to reactive species; formyl substrates were 7 to 8 times more active than acetylated compounds. The microsomal activities and the formyl-preferring soluble enzyme were inhibited by diethyl-p-nitrophenylphosphate, a microsomal deacylase inhibitor. The cytosolic enzymes that are most active with the acetyl and propionyl substrates were little affected by this organophosphate compound. The microsomal activation was not due solely to deacylation of the hydroxamic acid, since formylated and acetylated substrates were hydrolyzed at approximately the same rates.