TY - JOUR T1 - Xanthine Oxidase-Catalyzed Metabolism of 2-Nitrofluorene, a Carcinogenic Air Pollutant, in Rat Skin JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 367 LP - 372 DO - 10.1124/dmd.31.4.367 VL - 31 IS - 4 AU - Osamu Ueda AU - Shigeyuki Kitamura AU - Koji Ohashi AU - Kazumi Sugihara AU - Shigeru Ohta Y1 - 2003/04/01 UR - http://dmd.aspetjournals.org/content/31/4/367.abstract N2 - The reductive metabolism of 2-nitrofluorene, a carcinogenic air pollutant, in rat skin microsomes and cytosol was investigated. 2-Nitrofluorene was reduced to the corresponding amine by the microsomes with NADPH and by the cytosol with 2-hydroxypyrimidine or 4-hydroxypyrimidine under anaerobic conditions. The cytosolic activity was much higher than that of skin microsomes. The 2- or 4-hydroxypyrimidine-linked nitroreductase activity was inhibited by oxypurinol and (+/−)-8-(3-methoxy-4-phenylsulfinylphenyl) pyrazolo[1,5-a]-1,3,5-triazine-4(1H)-one (BOF-4272), inhibitors of xanthine oxidase, but not by menadione, chlorpromazine and isovanillin, inhibitors of aldehyde oxidase. When skin cytosol was applied to a DEAE-cellulose column, the fractions containing xanthine oxidase exhibited a marked 2-hydroxypyrimidine-linked nitroreductase activity. In contrast, the aldehyde oxidase fraction showed little activity. Nitroreductase fractions obtained by ion exchange chromatography showed a band in Western blotting analysis using anti-rat xanthine oxidase. Moreover, the xanthine oxidase fraction exhibited a significant nitroreductase activity in the presence of 2-hydroxypyrimidine, 4-hydroxypyrimidine or hypoxanthine, and these activities were inhibited by inhibitors of xanthine oxidase. These results indicated that reduction of 2-nitrofluorene in the skin was mainly catalyzed by xanthine oxidase. The American Society for Pharmacology and Experimental Therapeutics ER -