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Renal Reduced Nicotinamide Adenine Dinucleotide Phosphate:cytochrome c Reductase-mediated Metabolism of the Carcinogen N-[4-(5-Nitro-2-furyl)-2-thiazolyl]acetamide¹

Geriatric Research, Education, and Clinical Center, Veterans Administration Medical Center, St. Louis, Missouri 63125 [M. B. M., T. V. Z., M. O. P., B. B. D.]; and Departments of Internal Medicine [M. B. M., T. V. Z., B. B. D.] and Biochemistry [T. V. Z.], St. Louis University School of Medicine, St. Louis, Missouri 63104

N-[4-(5-Nitro-2-furyl)-2-thiazolyl]acetamide (NFTA) metabolism was examined in vitro using microsomes prepared from rat liver and renal cortex and from rabbit liver and renal cortex and outer and inner medulla. NFTA nitroreduction was observed with each tissue. Three mol of NADPH were used per mol of NFTA reduced. Substrate and inhibitor specificity suggested that the microsomal nitroreduction was due to NADPH:cytochrome c reductase. Metabolite(s) formed bound to protein, RNA, DNA, and synthetic polyribonucleotides. Maximum covalent binding was seen with polyguanylic acid. A guanosine-NFTA adduct was isolated. Binding was inhibited by sulfhydryl compounds and vitamin E. The [¹⁴C]NFTA:glutathione or [³H]glutathione:NFTA conjugates obtained from microsomal incubations showed identical chromatographic properties as the product obtained by the reaction of synthetic N-hydroxy-NFTA with [³H]glutathione. Structures of synthetic N-hydroxy-NFTA and the microsomal reduction product 1-[4-(2-acetylaminothiazolyl)]-3-cyano-1-propanone were established by mass spectrometry. The latter reduction product did not bind macromolecules. These results suggest that renal NADPH:cytochrome c reductase reduces NFTA to an N-hydroxy-NFTA intermediate that binds nucleophilic sites on macromolecules.

¹ This research was supported by the Veterans Administration and the American Cancer Society, Missouri Chapter. A preliminary report of this work was presented at the Annual Meeting of the American Association for Cancer Research, April 28 to May 1, 1983, San Diego, CA (24).

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

Received 12/13/83. Accepted 9/25/84.

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