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Effect of Peroxidase Inhibitors on an in Vivo Metabolite of the Urinary Bladder Carcinogen N-[4-(5-Nitro-2-furyl)-2-thiazolyl]formamide in Rats¹

Geriatric Research, Education, and Clinical Center, Veterans Administration Medical Center, St. Louis, Missouri 63125 [J. R. R., L. A. S., T. V. Z., B. B. D.], and Departments of Biochemistry [J. R. R., T. V. Z.] and Internal Medicine [L. A. S., T. V. Z., B. B. D.], St. Louis University School of Medicine, St. Louis, Missouri 63104

Peroxidase metabolism of 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) was evaluated in vitro and in vivo. In vitro metabolism of ANFT was characteristic of the hydroperoxidase activity of prostaglandin H synthase. The peroxidase inhibitors, 6-n-propyl-2-thiouracil and methimazole, significantly reduced ANFT binding to trichloroacetic acid precipitable material and glutathione conjugate formation. Isolated perfused kidneys rapidly converted the glutathione conjugate to its corresponding mercapturic acid (ANFT-MA). With both radiochemical and electrochemical techniques, ANFT-MA was identified in the urine of rats given N-[¹⁴C]-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide, the carcinogenic N-formyl analogue of ANFT. ANFT was the major urinary metabolite with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide not detected. A 30-min pretreatment with 6-n-propyl-2-thiouracil and methimazole significantly reduced urinary excretion of ANFT-MA in rats given N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (150 mg/kg) from 14.8 ± 2.1 (SE) to 7.9 ± 0.8 and 6.2 ± 1.1 nmol/18 h, respectively. Peroxidase inhibitor pretreatment did not alter the excretion of ANFT or prostaglandin E₂. These results provide further in vitro and in vivo support for the involvement of peroxidases, i.e., the hydroperoxidase activity of prostaglandin H synthase, in ANFT metabolism.

¹ This research was supported by the Veterans Administration and by Grant CA-28015 from the National Cancer Institute.

² Present address: Pfizer Incorporated, Groton, CT 06340.

³ To whom requests for reprints should be addressed, at Geriatric Center (111G-JB), VA Medical Center, St. Louis, MO 63125.

Received 3/26/86. Revised 8/19/86. Revised 3/ 6/87. Revised 7/ 6/87. Revised 10/15/87. Accepted 10/19/87.