title: Metabolism of drugs in the eye. Menadione-dependent reduction of tertiary amine N-oxide by preparations from bovine ocular tissues.
abstract: As described previously, the microsomes and cytosol from bovine ciliary body exhibited a significant reductase activity toward tertiary amine N-oxide such as imipramine N-oxide when supplemented with menadione. In the present study, the menadione-dependent N-oxide reduction was further examined with preparations of bovine ocular tissues. The reduction of imipramine N-oxide occurred much more significantly when the microsomes and cytosols from bovine ciliary body were supplemented with both menadione and NAD(P)H, compared with menadione alone. The cytosolic menadione-dependent reduction, but not the microsomal one, was markedly inhibited by dicumarol, suggesting the involvement of DT-diaphorase in the reaction. Localization of the menadione-dependent N-oxide reductase activity in bovine ocular tissues indicated that the highest activity resided in the ciliary body, followed by retinal pigment epithelium-choroid, iris, retina and cornea. When the cytosol from bovine ciliary body was fractionated with ammonium sulfate, the distribution of the menadione-dependent N-oxide reductase activity in the resultant fractions was parallel, but roughly, to that of DT-diaphorase activity, supporting the assumption that the flavoenzyme was involved in the cytosolic menadione-dependent N-oxide reduction. We proposed a new mechanism for the metabolic reduction of tertiary amine N-oxide in the eye: Menadione is reduced to the corresponding diol by quinone-reducing enzymes and then tertiary amine N-oxide is reduced by the diol to the corresponding amine nonenzymatically.
authors.affiliation: Department of Ophthalmology, Hiroshima University School of Medicine, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Shimada
authors.forename: H K
authors.initials: HK
authors.lastname: Mishima
authors.forename: H
authors.initials: H
authors.lastname: Nikaido
authors.forename: S
authors.initials: S
authors.lastname: Kitamura
authors.forename: K
authors.initials: K
authors.lastname: Tatsumi
mesh_terms: D000818:Animals; D002417:Cattle; D002924:Ciliary Body / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D005123:Eye / Q000201:enzymology / Q000378:metabolism*; D007099:Imipramine / Q000031:analogs & derivatives* / Q000378:metabolism; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D009249:NADP / Q000494:pharmacology; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D011808:Quinone Reductases / Q000378:metabolism; D014812:Vitamin K / Q000494:pharmacology*
chemical_list: D014812:Vitamin K; D009249:NADP; C002921:imipramine N-oxide; D010088:Oxidoreductases; D011808:Quinone Reductases; C063464:imipramine N-oxide reductase; D007099:Imipramine