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

Abstract

ABSTRACT: γ-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 μM 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) γ-carboxylation of clotting factors is regulated by glucocorticoids in the developing liver, and 2) dexamethasone stimulates intracellular γ-carboxylation of the factor X precursor by a mechanism that currently is unknown.

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