Sulfaquinoxaline inhibition of vitamin K epoxide and quinone reductase.
Sulfaquinoxaline (N1-(2-quinoxalinyl)sulfanilamide) has been shown to be a potent (Ki = 1 microM) freely reversible inhibitor of the dithiothreitol-dependent reduction of both vitamin K epoxide and vitamin K quinone by rat liver microsomes in vitro. This observation provides an explanation for the hemorrhagic syndrome occasionally seen in poultry on medicated feed and the efficacy of sulfaquinoxaline in anticoagulant based rodenticides. Sulfaquinoxaline inhibition resembled inhibition by coumarin anticoagulants (e.g., warfarin) and hydroxynaphthoquinones (e.g., lapachol). Inhibition was observed in assays using microsomes from control strain rats, but the enzyme was resistant to sulfaquinoxaline in microsomes from warfarin-resistant rats. Steady-state kinetics inhibition patterns were nearly competitive versus dithiothreitol and nearly uncompetitive versus vitamin K epoxide as is observed for warfarin and lapachol. These results suggest that this inhibitor binds to the oxidized form of vitamin K epoxide reductase in the same way as suggested for the coumarins and hydroxyquinones. Of 10 other sulfa drugs tested, none were inhibitors, and of fragments and related compounds tested, only 2-aminoquinoxaline benzenesulfonamide was active. These results provide a probably orientation in the binding site in relation to that for warfarin and lapachol.
Preusch
P C
PC
Department of Chemistry, University of Akron, Ohio 44325.
Hazelett
S E
SE
Lemasters
K K
KK
D000818:Animals; D004351:Drug Resistance; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction; D011808:Quinone Reductases / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D013424:Sulfanilamides / Q000494:pharmacology*; D013428:Sulfaquinoxaline / Q000494:pharmacology*; D010837:Vitamin K 1 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin
D013424:Sulfanilamides; C016186:vitamin K1 oxide; D014859:Warfarin; D010837:Vitamin K 1; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases; D011808:Quinone Reductases; D013428:Sulfaquinoxaline