title: NADPH-dependent oxidation of reduced ebselen, 2-selenylbenzanilide, and of 2-(methylseleno)benzanilide catalyzed by pig liver flavin-containing monooxygenase.
abstract: The selenazole ring-opened metabolites of ebselen, 2-selenylbenzanilide and 2-(methylseleno)benzanilide, are substrates for flavin-containing monooxygenase from pig liver. The Km values were 25 and 3 microM, respectively, measured at 37 degrees C, pH 7.4, in the presence of 1 mM GSH. The Vmax values were 390 mU/mg of protein, similar to those obtained with methimazole or other substrates for FMO1. Although ebselen also appears to be a substrate in the absence of GSH, it progressively inactivates the enzyme, apparently by binding covalently to essential enzyme thiols. The oxidation products of the selenol and methylseleno derivatives are rapidly reduced by GSH, regenerating the parent substrates. Rapid reduction of the selenide oxide by GSH was unexpected and suggests that, unlike S-oxidation of sulfides, Se-oxidation of selenides may be a route for bioactivation. The data show that in the presence of FMO1 micromolar amounts of either of these ring-opened metabolites establish a futile cycle catalyzing the oxidation of GSH to GSSG by NADPH and oxygen.
authors.affiliation: Institut für Physiologische Chemie I, Universität Düsseldorf, Germany.
authors.forename: D M
authors.initials: DM
authors.lastname: Ziegler
authors.forename: P
authors.initials: P
authors.lastname: Graf
authors.forename: L L
authors.initials: LL
authors.lastname: Poulsen
authors.forename: W
authors.initials: W
authors.lastname: Stahl
authors.forename: H
authors.initials: H
authors.lastname: Sies
mesh_terms: D000813:Anilides / Q000378:metabolism*; D000818:Animals; D001393:Azoles / Q000378:metabolism*; D002384:Catalysis; D005978:Glutathione / Q000378:metabolism; D054833:Isoindoles; D008099:Liver / Q000201:enzymology*; D009249:NADP / Q000378:metabolism; D016566:Organoselenium Compounds / Q000378:metabolism*; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000378:metabolism*; D013552:Swine
chemical_list: D000813:Anilides; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; C075952:2-selenylbenzanilide; C042986:ebselen; D009249:NADP; C068988:2-methylselenobenzanilide; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D005978:Glutathione