Reduction of N-hydroxy-sulfonamides, including N-hydroxy-valdecoxib, by the molybdenum-containing enzyme mARC.

Abstract

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.

• Authors: Antje Havemeyer, Sanja Grünewald, Bettina Wahl, Florian Bittner, Ralf Mendel, Péter Erdélyi, János Fischer, Bernd Clement
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 38 Issue 11 Pg. 1917-21 (Nov 2010) ISSN: 1521-009X [Electronic] United States
• PMID: 20699408 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Isoxazoles
• Metalloproteins
• Mitochondrial Proteins
• N-hydroxy-valdecoxib
• Prodrugs
• Sulfonamides
• Molybdenum
• Cytochromes b5
• Oxidoreductases
• mitochondrial amidoxime reducing component 1, human
• mitochondrial amidoxime reducing component 2, human
• Cytochrome-B(5) Reductase

Topics

• Animals
• Chromatography, High Pressure Liquid
• Cytochrome-B(5) Reductase (genetics, metabolism)
• Cytochromes b5 (genetics, metabolism)
• Electrophoresis, Polyacrylamide Gel
• Humans
• In Vitro Techniques
• Isoxazoles (chemistry, metabolism)
• Metabolic Detoxication, Phase I
• Metalloproteins (genetics, metabolism)
• Microsomes, Liver (drug effects, enzymology)
• Mitochondria (drug effects, enzymology)
• Mitochondrial Proteins (genetics, metabolism)
• Molecular Structure
• Molybdenum (metabolism)
• Oxidation-Reduction
• Oxidoreductases (genetics, metabolism)
• Prodrugs (chemistry, metabolism)
• Substrate Specificity
• Sulfonamides (chemistry, metabolism)
• Swine
• Transfection