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Metabolic Activation of Carcinogenic Aromatic Amines by Dog Bladder and Kidney Prostaglandin H Synthase¹

Geriatric Research, Education, and Clinical Center, Veterans Administration Medical Center, St. Louis 63125 [T. V. Z., B. B. D.], and Departments of Biochemistry [R. W. W., T. V. Z.] and Internal Medicine [T. V. Z., B. B. D.], St. Louis University School of Medicine, St. Louis, Missouri 63104, and National Center for Toxicological Research, Jefferson, Arkansas 72079 [F. F. K.]

Microsomal enzyme preparations from dog liver, kidney, and bladder were used to assess the prostaglandin H synthasecatalyzed activation of carcinogenic aromatic amines to bind covalently to proteins and nucleic acids. Benzidine, a urinary bladder carcinogen, bound to protein of bladder transitional epithelial and renal inner and outer medullary microsomes and was dependent upon addition of arachidonic acid, but not upon reduced nicotinamide adenine dinucleotide phosphate. Bladder transitional epithelial microsomes also activated o-dianisidine, 4-aminobiphenyl, and 2-naphthylamine to bind to protein and transfer RNA and benzidine and o-dianisidine to bind DNA. Cosubstrate and inhibitor specificities were consistent with activation by prostaglandin H synthase. Binding of benzidine to protein was not observed with either hepatic or renal cortical microsomes upon addition of arachidonic acid or reduced nicotinamide adenine dinucleotide phosphate.

Prostaglandin H synthase and mixed-function oxidase-catalyzed bindings of 2-naphthylamine to protein and to transfer RNA were compared using liver and bladder microsomes. Only mixed-function oxidase-catalyzed binding was observed in liver, and only prostaglandin H synthase-catalyzed binding was observed in bladder. The rate of binding catalyzed by bladder microsomes was considerably greater than that catalyzed by hepatic microsomes. In addition, the bladder content of prostaglandin H synthase activity was approximately 10 times that of kidney inner medullary, a tissue reported to have a relatively high content of this enzyme in other species. These results are consistent with involvement of bladder transitional epithelial prostaglandin H synthase in the genesis of primary aromatic amine-induced bladder cancer.

¹ This work was supported by the Veterans Administration, the Environmental Protection Agency, and the National Center for Toxicological Research.

² To whom requests for reprints should be addressed, at Geriatric Center (111G-JB), VA Medical Center, St. Louis, MO 63125.

Received 10/31/83. Accepted 1/27/84.

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