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Relationship of Metabolic Activation of N-Hydroxy-N-acylarylamines to Biological Response in the Liver and Mammary Gland of the Female CD Rat¹

Department of Chemical Carcinogenesis, Michigan Cancer Foundation, Detroit, Michigan 48201

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 -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 acids, since formylated and acetylated substrates were hydrolyzed at approximately the same rates.

¹ The studies in this report from the A. Alfred Taubman Facility were supported by USPHS Grant CA23386 from the National Cancer Institute and an Institutional grant from the United Foundation of Detroit.

² Present address: First Department of Pathology, Nagoya City University Medical School, Nagoya 467, Japan.

³ To whom requests for reprints should be addressed.

Received 9/ 8/80. Accepted 7/23/81.