RT Journal Article SR Electronic T1 A Unique Tertiary Amine N-Oxide Reduction System Composed of Quinone Reductase and Heme in Rat Liver Preparations JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 92 OP 97 VO 27 IS 1 A1 Shigeyuki Kitamura A1 Kazumi Sugihara A1 Kiyoshi Tatsumi YR 1999 UL http://dmd.aspetjournals.org/content/27/1/92.abstract AB The results of this study show the quinone-dependent reduction of tertiary amine N-oxides to the corresponding tertiary amines by rat liver preparations. The reduction of imipramineN-oxide to imipramine mediated by liver mitochondria, microsomes, and cytosol proceeded in the presence of both NAD(P)H and menadione under anaerobic conditions. When menadione was replaced with 1,4-naphthoquinone or 9,10-anthraquinone, similar results were obtained in the cytosolic reduction. The quinone-dependent reducing activity in liver cytosol was inhibited by dicumarol and carbon monoxide. This result suggested that the activity is caused by DT-diaphorase, a cytosolic quinone reductase, and hemoproteins in liver cytosol. In fact, catalase and hemoglobin showed the ability to reduce imipramineN-oxide when supplemented with DT-diaphorase. The hemoproteins also exhibited the N-oxide reductase activity with reduced menadione, menadiol. The N-oxide reductase activity of the hemoproteins was also exhibited with 1,4-dihydroxynaphthalene, 1,4,9,10-tetrahydroxyanthracene, or 1,4-dihydroxy-9,10-anthraquinone. Furthermore, hematin revealed a significant N-oxide-reducing activity in the presence of menadiol. The reduction appears to proceed in two steps. The first step is reduction of menadione to menadiol by a quinone reductase with NADPH or NADH. The second step is nonenzymatic reduction of tertiary amineN-oxides to tertiary amines by menadiol, catalyzed by the heme group of hemoproteins. Cyclobenzaprine N-oxide and brucine N-oxide were also transformed similarly to the corresponding amine by the quinone-dependent reducing system. The American Society for Pharmacology and Experimental Therapeutics