PT  - JOURNAL ARTICLE
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
TI  - Carbon-Carbon Bond Cleavage in Activation of the Prodrug Nabumetone
AID  - 10.1124/dmd.114.056903
DP  - 2014 May 01
TA  - Drug Metabolism and Disposition
PG  - 828--838
VI  - 42
IP  - 5
4099  - http://dmd.aspetjournals.org/content/42/5/828.short
4100  - http://dmd.aspetjournals.org/content/42/5/828.full
SO  - Drug Metab Dispos2014 May 01; 42
AB  - 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.