Carbon-carbon bond cleavage in activation of the prodrug nabumetone.
Drug Metab Dispos
; 42(5): 828-38, 2014 May.
Article
em En
| MEDLINE
| ID: mdl-24584631
ABSTRACT
Carbon-carbon bond cleavage reactions are catalyzed by, among others, lanosterol 14-demethylase (CYP51), cholesterol side-chain cleavage enzyme (CYP11), sterol 17ß-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.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Butanonas
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Pró-Fármacos
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Citocromo P-450 CYP1A2
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Inibidores de Ciclo-Oxigenase 2
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Ácidos Naftalenoacéticos
Limite:
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article