PT  - JOURNAL ARTICLE
AU  - Arora, Vinod K.
AU  - Philip, Thomas
AU  - Huang, Stella
AU  - Shu, Yue-Zhong
TI  - A Novel Ring Oxidation of 4- or 5-Substituted 2H-Oxazole to Corresponding 2-Oxazolone Catalyzed by Cytosolic Aldehyde Oxidase
AID  - 10.1124/dmd.112.044545
DP  - 2012 Sep 01
TA  - Drug Metabolism and Disposition
PG  - 1668--1676
VI  - 40
IP  - 9
4099  - http://dmd.aspetjournals.org/content/40/9/1668.short
4100  - http://dmd.aspetjournals.org/content/40/9/1668.full
SO  - Drug Metab Dispos2012 Sep 01; 40
AB  - The ring oxidation of 2H-oxazole, or C2-unsubstituted oxazole, to 2-oxazolone, a cyclic carbamate, was observed on various 4- or 5-substituted oxazoles. Using 5-(3-bromophenyl)oxazole as a model compound, its 2-oxazolone metabolite M1 was fully characterized by liquid chromatography/tandem mass spectrometry and nuclear magnetic resonance. The reaction mainly occurred in the liver cytosolic fraction without the requirement of cytochrome P450 enzymes and cofactor NADPH. Investigations into the mechanism of formation of 2-oxazolone using various chemical inhibitors indicated that the reaction was primarily catalyzed by aldehyde oxidase and not by xanthine oxidase. In addition, cytosol incubation of 5-(3-bromophenyl)oxazole in the medium containing H218O led to the 18O incorporation into M1, substantiating the reaction mechanism of a typical molybdenum hydroxylase. The rank order of liver cytosols for the 2-oxazolone formation was mouse > monkey ≫ rat and human liver cytosol, whereas M1 was not formed in dog liver cytosol. Because the reaction was observed with a number of 4- or 5-substituted 2H-oxazoles in mouse liver cytosols, 2H-oxazoles represent a new substrate chemotype for ring oxidation catalyzed by aldehyde oxidase.