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

Peroxidase metabolism of 2-amino-4-(5-nitro-2-fiiryl)thiazole (ANFI") was evaluated in vitro and in rivo. IH 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 electro chemical techniques, ANFT-MA was identified in the urine of rats given 7V-(uC]-|4-(S-nitro-2-furyl)-2-thiazolyl]formamide, the carcinogenic Nformyl analogue of ANFT. ANFT was the major urinary metabolite with 7V-|4-(5-mtro-2-furyl)-2-thiazolyl]formamide not detected. A 30-min pretreatmeni with 6-n-propyl-2-thiouracil and methimazole significantly re duced urinary excretion of ANFT-MA in rats given yV-[4-(5-nitro-2fiiryl>-2-thiazolyl]forinamide (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 pretreat ment 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.