In vivo effects of β-lactam antibiotics and heterocyclic thiol compounds on vitamin K-dependent carboxylation activity and blood coagulation factors in vitamin K-deficient rats

Abstract

The vivo effects of heterocyclic thiol compounds, corresponding to the 3′-position substituents of several β-lactam antibiotics, on blood coagulation factors and on liver microsomal γ-glutamylcarboxylation (γ-carboxylation) activity were evaluated in rats maintained on a vitamin K-deficient diet. These rats, when compared to normal control animals, exhibited hypoprothrombinemic changes: prolongation of both prothrombin time and activated partial thromboplastin time, decreases in factor VII and plasma prothrombin, and increases in PIVKA II (descarboxyprothrombin) both in plasma and liver. They also displayed a marked increase in liver microsomal γ-carboxylation activity. These blood coagulation variables could be altered markedly by administering various heterocyclic thiol compounds to the vitamin K-deficient rats, although these compounds did not inhibit γ-carboxylation activity in an assay system using phylloquinone. A similar pattern of alteration was observed when some β-lactam antibiotics were administered. Increased microsomal γ-carboxylation activity in antibiotic-treated vitamin K-deficient rats was normalized by the administration of vitamin K, concomitant with the recovery of blood coagulation variables to the normal range. The results indicate that antibiotic-induced hypoprothrombinemia in vivo is not caused by inhibition of enzymes of the γ-carboxylation system, such as vitamin K reductase and γ-glutamylcarboxylase, but is related to the endogenous vitamin K level.