Reduction of N-hydroxy-sulfonamides, including N-hydroxy-valdecoxib, by the molybdenum-containing enzyme mARC.
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 b(5) and b(5) 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.
Havemeyer
Antje
A
Institute of Pharmacy, Christian-Albrechts-University of Kiel, Kiel, Germany.
Grünewald
Sanja
S
Wahl
Bettina
B
Bittner
Florian
F
Mendel
Ralf
R
Erdélyi
Péter
P
Fischer
János
J
Clement
Bernd
B
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D042966:Cytochrome-B(5) Reductase / Q000235:genetics / Q000378:metabolism; D015786:Cytochromes b5 / Q000235:genetics / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000737:chemistry / Q000378:metabolism*; D050216:Metabolic Detoxication, Phase I; D008667:Metalloproteins / Q000235:genetics / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D008982:Molybdenum / Q000378:metabolism; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism*; D013552:Swine; D014162:Transfection
D007555:Isoxazoles; D008667:Metalloproteins; D024101:Mitochondrial Proteins; C530909:N-hydroxy-valdecoxib; D011355:Prodrugs; D013449:Sulfonamides; D008982:Molybdenum; D015786:Cytochromes b5; D010088:Oxidoreductases; C554553:MTARC1 protein, human; C554552:mitochondrial amidoxime reducing component 2, human; D042966:Cytochrome-B(5) Reductase