Chen Xin, Wei Qianhan, Lu Qianqian, Zhao Zeting, Yu Zhengrong, Zhang Yumei
Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, PR China.
Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, PR China.
Res Vet Sci. 2019 Jun;124:399-405. doi: 10.1016/j.rvsc.2019.05.002. Epub 2019 May 6.
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.
脱氢乙酸钠（Na-DHA）是一种可抑制细菌、真菌和酵母菌生长的抗菌剂，被用作动物饲料、食品及化妆品中的防腐剂。我们之前报道过Na-DHA会在Wistar大鼠中诱发凝血异常，但Na-DHA的抗凝机制仍有待确定。在此我们报道，Na-DHA可延长雄性和雌性Wistar大鼠的凝血酶原时间（PT）及活化部分凝血活酶时间（APTT）。此外，Na-DHA会降低大鼠血清中的维生素K（VK）水平，并提高维生素K缺乏/拮抗剂-II诱导蛋白（PIVKA-II）的水平。而且，我们发现用VK进行治疗不仅可逆转Na-DHA降低的血清VK水平及升高的PIVKA-II水平，还可减弱Na-DHA延长的PT和APTT，这表明Na-DHA降低的血清VK水平是其导致抗凝作用的原因。进一步地，我们发现Na-DHA抑制了Wistar大鼠肝脏组织中的维生素K环氧化物还原酶复合体亚基1（VKORC1），这是VK循环中的关键酶；Na-DHA处理后VKORC1的mRNA和蛋白水平降低即证明了这一点。综上所述，我们的数据表明，Na-DHA抑制肝脏VKORC1，导致血清VK水平下降，进而致使大鼠凝血异常。
