TY - JOUR T1 - Carbon-Carbon Bond Cleavage in Activation of the Prodrug Nabumetone JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 828 LP - 838 DO - 10.1124/dmd.114.056903 VL - 42 IS - 5 AU - Fatbardha Varfaj AU - Siti N. A. Zulkifli AU - Hyoung-Goo Park AU - Victoria L. Challinor AU - James J. De Voss AU - Paul R. Ortiz de Montellano Y1 - 2014/05/01 UR - http://dmd.aspetjournals.org/content/42/5/828.abstract N2 - Carbon-carbon bond cleavage reactions are catalyzed by, among others, lanosterol 14-demethylase (CYP51), cholesterol side-chain cleavage enzyme (CYP11), sterol 17β-lyase (CYP17), and aromatase (CYP19). Because of the high substrate specificities of these enzymes and the complex nature of their substrates, these reactions have been difficult to characterize. A CYP1A2-catalyzed carbon-carbon bond cleavage reaction is required for conversion of the prodrug nabumetone to its active form, 6-methoxy-2-naphthylacetic acid (6-MNA). Despite worldwide use of nabumetone as an anti-inflammatory agent, the mechanism of its carbon-carbon bond cleavage reaction remains obscure. With the help of authentic synthetic standards, we report here that the reaction involves 3-hydroxylation, carbon-carbon cleavage to the aldehyde, and oxidation of the aldehyde to the acid, all catalyzed by CYP1A2 or, less effectively, by other P450 enzymes. The data indicate that the carbon-carbon bond cleavage is mediated by the ferric peroxo anion rather than the ferryl species in the P450 catalytic cycle. CYP1A2 also catalyzes O-demethylation and alcohol to ketone transformations of nabumetone and its analogs. ER -