Dexamethasone stimulates vitamin K-dependent carboxylase activity in neonatal rats and cultured fetal hepatocytes.
gamma-Carboxylation of vitamin K-dependent clotting factors may be a key regulatory element in output of these proteins from liver to blood in the developing neonate. We have investigated the effect of hormones and growth factor on the vitamin K-dependent carboxylation system in neonatal rats and cultured fetal hepatocytes. Of the hormones and growth factor tested, only dexamethasone had a significant effect on the system. When dexamethasone was administered to newborn rats, there was a delayed response that produced significant enhancement of carboxylase activity 6 d after injection of the drug. A similar delayed response to the drug could also be demonstrated in cultured fetal hepatocytes. When cultured in the presence of 0.1-1 microM dexamethasone, cellular carboxylase activity was little affected by the drug the first 2 d of culture but the activity was increased more than threefold by 4 d in culture. Microsomal membranes from neonatal rat livers and fetal hepatocytes treated with dexamethasone showed enhanced vitamin K-dependent 14C labeling of the factor X membrane precursor pool. Enhanced labeling of the factor X membrane precursor pool has also been demonstrated in rats and HepG2 cells treated with warfarin. The data suggest that 1) gamma-carboxylation of clotting factors is regulated by glucocorticoids in the developing liver, and 2) dexamethasone stimulates intracellular gamma-carboxylation of the factor X precursor by a mechanism that currently is unknown.
Wallin
R
R
Department of Medicine, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27103.
Hutson
S M
SM
D000818:Animals; D000831:Animals, Newborn; D019735:Carbon-Carbon Ligases; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D005170:Factor X / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000201:enzymology; D008025:Ligases / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains
D003907:Dexamethasone; D005170:Factor X; D008025:Ligases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase