Dexamethasone Stimulates Vitamin K-Dependent Carboxylase Activity in Neonatal Rats and Cultured Fetal Hepatocytes

Abstract

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.