Comparison of rat liver response to coumarin administered in vivo versus in vitro

Abstract

Warfarin added to incubated liver slices inhibits the synthesis of factor VII (proconvertin) in proportion to the log of its concentration; surprisingly, it has the same inhibitory effect on the transport and incorporation of amino acid into protein of the liver slices. This latter finding seems to support the frequently proposed concept that vitamin K has a role in oxidative phosphorylation and that coumarin compounds, by antagonizing vitamin K, uncouple oxidative phosphorylation and thus have a general effect on cell energy supply. However, when we studied the liver of rats depleted of vitamin K the same effect was not seen. Liver slices from such animals produced little factor VII but they incorporated amino acid at the normal rate. Furthermore, administration of warfarin in vivo had the same result as vitamin K depletion: a fall in circulating prothrombin complex but no decrease in either labeling of plasma proteins by intravenous C14-amino acid or incorporation of amino acid into subsequently excised liver slices. There is thus a striking discrepancy between the action of warfarin administered in vitro and that administered in vivo.