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Drug Metabolism and Disposition Fast Forward
First published on October 7, 2005; DOI: 10.1124/dmd.105.006890

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Received for publication August 15, 2005.
Revised October 3, 2005.
Accepted for publication October 4, 2005.

ROLE OF HUMAN CYCLOOXYGENASE-2 IN THE BIOACTIVATION OF DAPSONE AND SULFAMETHOXAZOLE

Piyush M Vyas 1, Sanjoy Roychowdhury 1, Craig Svensson 1*

1 The University of Iowa

* Address correspondence to: E-mail: craig-svensson{at}uiowa.edu

Abstract

Sulfamethoxazole (SMX) and dapsone (DDS) are believed to mediate their adverse effects subsequent to bioactivation to their respective arylhydroxylamine and arylnitroso metabolites, resulting in covalent adduct formation with intracellular proteins. Various bioactivating enzymes, such as cytochromes P450 and myeloperoxidase have been shown to be capable of catalyzing the N-oxidation of these compounds. We assessed the role of human cyclooxygenase-2 (COX-2) in the metabolism and subsequent adduct formation of DDS and SMX using recombinant human COX-2. Utilizing an adduct-specific ELISA assay, we found that the complete enzyme system gave rise to covalent adducts. However, the non-specific COX inhibitor indomethacin did not reduce the amount of covalent adduct formed. Formation of the arylhydroxylamine metabolites was demonstrated via high performance liquid chromatography coupled with UV absorption. Metabolite formation was found to be secondary to the H2O2 in the incubation mixture and was not enzyme mediated. Hence, COX-2 does not play a direct role in the bioactivation of these parent drugs to their arylhydroxylamine metabolites.


Key words: covalent drug binding, cyclooxygenases, idiosyncratic drug reactions


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