RT Journal Article
SR Electronic
T1 Reduction of <em>N</em>-Hydroxy-sulfonamides, Including <em>N</em>-Hydroxy-valdecoxib, by the Molybdenum-Containing Enzyme mARC
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1917
OP 1921
DO 10.1124/dmd.110.032813
VO 38
IS 11
A1 Antje Havemeyer
A1 Sanja Grünewald
A1 Bettina Wahl
A1 Florian Bittner
A1 Ralf Mendel
A1 Péter Erdélyi
A1 János Fischer
A1 Bernd Clement
YR 2010
UL http://dmd.aspetjournals.org/content/38/11/1917.abstract
AB Purification of the mitochondrial enzyme responsible for reduction of N-hydroxylated amidine prodrugs led to the identification of two newly discovered mammalian molybdenum-containing proteins, the mitochondrial amidoxime reducing components mARC-1 and mARC-2 (Gruenewald et al., 2008). These 35-kDa proteins represent a novel group of molybdenum proteins in eukaryotes as they form a molybdenum cofactor-dependent enzyme system consisting of three separate proteins (Havemeyer et al., 2006). Each mARC protein reduces N-hydroxylated compounds after reconstitution with the electron transport proteins cytochrome b5 and b5 reductase. In continuation of our drug metabolism investigations (Havemeyer et al., 2006; Gruenewald et al., 2008), we present data from reconstituted enzyme systems with recombinant human and native porcine enzymes showing the reduction of N-hydroxy-sulfonamides (sulfohydroxamic acids) to sulfonamides: the N-hydroxy-sulfonamide N-hydroxy-valdecoxib (N-hydroxy-4-[5-methyl-3-phenyl-4-isoxazolyl]-benzenesulfonamide) represents a novel cyclooxygenase (COX)-2 inhibitor and is therefore a drug candidate in the treatment of diseases associated with rheumatic inflammation, pain, and fever. It was synthesized as an analog of the known COX-2 inhibitor valdecoxib (4-[5-methyl-3-phenyl-4-isoxazolyl]-benzenesulfonamide) (Talley et al., 2000). N-Hydroxy-valdecoxib had low in vitro COX-2 activity but showed significant analgesic activity in vivo and a prolonged therapeutic effect compared with valdecoxib (Erdélyi et al., 2008). In this report, we demonstrate that N-hydroxy-valdecoxib is enzymatically reduced to its pharmacologically active metabolite valdecoxib. Thus, N-hydroxy-valdecoxib acts as prodrug that is activated by the molybdenum-containing enzyme mARC.