Species comparison of vitamin K1 2,3-epoxide reductase activity in vitro: kinetics and warfarin inhibition.
A comparative study of vitamin K(1) 2,3-epoxide reductase (VKOR) activity in vitro was conducted across species. The apparent kinetic constants K(m app), V(max), and Cl(int app) were determined in bovine, canine, equine, human, murine, ovine, porcine, and rat hepatic microsomes. In addition to these enzyme kinetic constants, the IC(50) of warfarin for VKOR was determined in human, murine, porcine, and rat hepatic microsomes. Interspecies differences were observed when comparing the K(m app) (range, 2.41-6.46 microM), V(max) (range, 19.5-85.7 nmol/mg/min), and Cl(int app) (range, 8.2-18.4 ml/mg/min) values. Comparison of the IC(50) values of warfarin, across the four species tested, revealed a significant species difference between murine microsomes (0.17 microM) and rat microsomes (0.07 microM). Overall, this study indicates that there are interspecies differences regarding the in vitro reduction of vitamin K(1) 2,3-epoxide by the warfarin-sensitive enzyme vitamin K(1) 2,3-epoxide reductase. Significant differences between the IC(50) values of murine and rat microsomes suggest differences in the susceptibility of these species to warfarin.
Wilson
Christina R
CR
Animal Disease Diagnostic Laboratory, Purdue University, 1175 ADDL, 460 South University, West Lafayette, IN 47907-2065, USA.
Sauer
John-Michael
JM
Carlson
Gary P
GP
Wallin
Reidar
R
Ward
Michael P
MP
Hooser
Stephen B
SB
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D002417:Cattle; D004285:Dogs; D005260:Female; D006736:Horses; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D012756:Sheep; D013045:Species Specificity; D013552:Swine; D014812:Vitamin K / Q000378:metabolism*; D010837:Vitamin K 1 / Q000031:analogs & derivatives* / Q000378:metabolism*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000494:pharmacology*
D000925:Anticoagulants; D014812:Vitamin K; C016186:vitamin K1 oxide; D014859:Warfarin; D010837:Vitamin K 1; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases