The in vivo effects of acenocoumarol, phenprocoumon and warfarin on vitamin K epoxide reductase and vitamin K-dependent carboxylase in various tissues of the rat.
In rats the in vivo effects of a chronic low-dose treatment (+/- 60 micrograms/rat per day) with different coumarins (acenocoumarol, phenprocoumon and warfarin) on hepatic and non-hepatic vitamin K-dependent enzyme systems were compared. The plasma concentrations of the three coumarins differed largely but these differences were not reflected in the microsomal coumarin contents. The non-hepatic microsomes contained less than 20% of the coumarins found in liver microsomes. No substantial differences were observed between the following effects of the three anticoagulant treatments. The blood coagulation factor activities were about 10% of normal. The hepatic microsomal vitamin K epoxide reductase activity was diminished to about 35% of control values. The vitamin K epoxide reductase activities present in kidney, lung, spleen, testis and brain microsomes were less influenced by the coumarin treatments; activities ranged between 45 and 65% of normal. In the liver microsomes a 15-fold accumulation of non-carboxylated precursor proteins was found; in the non-hepatic microsomes this effect was less pronounced but still present. The hepatic vitamin K-dependent carboxylase activity was enhanced but the corresponding non-hepatic enzyme activities were slightly or not affected. In addition, the effects of a chronic low-dose warfarin treatment were compared with those after an acute high dose of the drug.
D015110:4-Hydroxycoumarins / Q000494:pharmacology*; D000074:Acenocoumarol / Q000494:pharmacology*; D000818:Animals; D019735:Carbon-Carbon Ligases; D007668:Kidney / Q000201:enzymology; D008025:Ligases / Q000378:metabolism*; D008168:Lung / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010644:Phenprocoumon / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000201:enzymology; D013737:Testis / Q000201:enzymology; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000494:pharmacology*
D015110:4-Hydroxycoumarins; D014859:Warfarin; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases; D008025:Ligases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase; D000074:Acenocoumarol; D010644:Phenprocoumon