RT Journal Article
SR Electronic
T1 ROLE OF HUMAN CYCLOOXYGENASE-2 IN THE BIOACTIVATION OF DAPSONE AND SULFAMETHOXAZOLE
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 16
OP 18
DO 10.1124/dmd.105.006890
VO 34
IS 1
A1 Piyush M. Vyas
A1 Sanjoy Roychowdhury
A1 Craig K. Svensson
YR 2006
UL http://dmd.aspetjournals.org/content/34/1/16.abstract
AB Sulfamethoxazole (SMX) and dapsone (4,4′-diaminodiphenylsulfone, 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. Using an adduct-specific enzyme-linked immunosorbent assay, we found that the complete enzyme system gave rise to covalent adducts. However, the nonspecific 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. The American Society for Pharmacology and Experimental Therapeutics