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Aspirin Inhibition of N-[4-(5-Nitro-2-furyl)-2-thiazolyl]formamide-induced Lesions of the Urinary Bladder Correlated with Inhibition of Metabolism by Bladder Prostaglandin Endoperoxide Synthetase¹

Department of Pathology [S. M. C., G. M., S. F.], St. Vincent Hospital, Worcester, Massachusetts 01604, and Geriatric Research, Education, and Clinical Center [T. V. Z., M. B. M., N. S. R., B. B. D.], VA Medical Center, St. Louis, Missouri 63125

The effects of aspirin on N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide (FANFT) -induced urinary bladder lesions, endogenous bladder prostaglandin E₂ synthesis, and the metabolism of FANFT by bladder epithelial microsomes were examined. Rats were fed 0.5% aspirin and/or a diet containing 0.1% or 0.2% FANFT. Bladder lesions were observed with light and scanning electron microscopy, and the prostaglandin E₂ content of rat bladder was measured by radioimmunoassay. Metabolism of FANFT was measured by decreased absorbance at 400 nm. Aspirin inhibited the appearance of hyperplastic lesions induced by feeding 0.1% or 0.2% FANFT for 6 or 12 weeks. Aspirin reduced bladder prostaglandin E₂ content at 1, 2, 6, and 13 weeks compared to corresponding control values. Rat and rabbit microsomal metabolism of FANFT were dependent upon specific fatty acid substrates and prevented by specific inhibitors (including aspirin) of prostaglandin endoperoxide synthetase. Other inhibitor and substrate specificity studies suggest that FANFT was not metabolized by xanthine oxidase, lipoxygenase, lipid peroxidation, or mixed-function oxidases. These results suggest that the metabolism of FANFT by prostaglandin endoperoxide synthetase may be involved in the metabolic activation of FANFT necessary for the induction of bladder cancer in rats.

¹ Supported in part by USPHS Grants CA-15945 and CA-28015, from the National Cancer Institute through the National Bladder Cancer Project.

² To whom requests for reprints should be addressed, Department of Pathology, University of Nebraska Medical Center, 42nd and Dewey Ave., Omaha, Nebr. 68105.

³ Present address: First Department of Pathology, Nagoya City University Medical School, Nagoya 467, Japan.

Received 11/14/80. Accepted 6/ 4/81.