Vitamin K-dependent carboxylation in the developing rat: evidence for a similar mechanism of action of warfarin in fetal and adult livers.
Our report presents data on maturation of the vitamin K-dependent carboxylation system in fetal and neonatal rat livers. This system which converts precursors of clotting factors II, VII, IX, X, protein S, and protein C to gamma-carboxylated proteins exhibited low gamma-carboxylation activity before birth. However, around the time of birth there was a sudden increase in all enzyme activities associated with the vitamin K-dependent carboxylation system. In 2-d neonatal rats these activities dropped to levels that were measured in fetal livers whereupon the activities had risen to adult levels in 7-d neonatal rats. However, the activities of the two pathways that provide the carboxylase with reduced vitamin KH2 cofactor were never as high as that measured in maternal livers. It appeared that the pathway which is insensitive to coumarin anticoagulant drugs matures later than the coumarin drug-sensitive pathway. This conclusion is supported by the finding of a late appearance in development of the vitamin K-reducing enzyme DT-diaphorase. Warfarin, when administered to the mother, affected the fetal livers at all stages of development studied (d 16-21). This was clearly demonstrated by vitamin K-dependent 14C-labeling of a 70-kD liver protein that has been shown previously to be a marker for the effect of this drug on the liver. The data demonstrate a similar mechanism of action of warfarin in fetal and neonatal rat livers and an ongoing maturation process of the vitamin K-dependent carboxylation system in these rats.
Wallin
R
R
Department of Medicine, Bowman Gray School of Medicine, Winston-Salem, North Carolina 27103.
D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D019735:Carbon-Carbon Ligases; D005260:Female; D005333:Fetus / Q000378:metabolism*; D008025:Ligases / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000196:embryology / Q000201:enzymology* / Q000254:growth & development; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D016660:NAD(P)H Dehydrogenase (Quinone); D011247:Pregnancy; D011808:Quinone Reductases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014859:Warfarin / Q000494:pharmacology*
D014859:Warfarin; D016660:NAD(P)H Dehydrogenase (Quinone); D011808:Quinone Reductases; D008025:Ligases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase