Sodium dehydroacetate induces coagulation dysfunction by inhibiting liver vitamin K epoxide reductase complex subunit...

Sodium dehydroacetate (Na-DHA), an antibiotic agent that combats growth of bacteria, fungi, and yeast, is used as a preservative in animal feed, food, and cosmetics. We previously reported that Na-DHA induces coagulation anomalies in Wistar rats, but the anticoagulant mechanism of Na-DHA remains to be established. Here we report that Na-DHA prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT) in male and female Wistar rats. In addition, Na-DHA decreased vitamin K (VK) levels and increased the levels of protein induced by vitamin K absence/antagonist-II (PIVKA-II) in rat serum. Moreover, we found that treatment with VK not only reversed Na-DHA-decreased serum VK and -increased PIVKA-II levels, but also attenuated Na-DHA-prolonged PT and APTT, suggesting that Na-DHA-decreased serum VK level contributes to the anticoagulation due to Na-DHA. Further we found that Na-DHA inhibited vitamin K epoxide reductase complex subunit 1 (VKORC1), a key enzyme in VK recycling, in the liver tissue of Wistar rats, as evidenced by reduced mRNA and protein levels of VKORC1 following Na-DHA treatment. Taken together, our data indicate that Na-DHA inhibits liver VKORC1, resulting in a decrease of serum VK levels, leading to abnormal coagulation in rats.