Anticoagulant effect of sodium dehydroacetate (DHA-S) in rats.
Sodium dehydroacetate (DHA-S) is used as a food additive, preservative and antimicrobial agent. Repeated oral administration of DHA-S in rats induced severe hemorrhage in multiple organs and prolongation of blood coagulation factors. To determine the mechanism of hemorrhage, the protective effect of vitamin K (VK) was investigated. Increased VK-dependent blood coagulation parameters, a prolonged prothrombin time (PT) and an activated partial thromboplastin time (APTT) were observed in rats when DHA-S alone was administered, while only a slight change was observed in animals that received a single injection of vitamin K2 following the DHA-S dosing. These results suggest that DHA-S-induced hemorrhage is caused by a deficiency of vitamin K. In addition, the inhibitory effect of DHA-S on vitamin K1 epoxide reductase (VKOR) activity was measured with an in vitro system using liver microsomes of normal male rats. DHA-S concentration-dependently inhibited VKOR activity similar to warfarin, but the inhibitory concentration was high. Therefore, it was concluded that the DHA-S-induced hemorrhage was caused by a depletion of blood VK, associated with any factors including VKOR inhibition.
Sakaguchi
Yuka
Y
Toxicology and Pharmacokinetics Laboratories, Pharmaceutical Research Laboratories, Toray Industries, Inc., 10-1, Tebiro 6-chome, Kamakura, Kanagawa 248-8555, Japan.
Suga
Sachiko
S
Oshida
Keiyu
K
Miyamoto-Kuramitsu
Keiko
K
Ueda
Kohei
K
Miyamoto
Yohei
Y
D000818:Animals; D000925:Anticoagulants / Q000633:toxicity*; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity; D005503:Food Additives / Q000633:toxicity*; D006470:Hemorrhage / Q000097:blood / Q000139:chemically induced* / Q000517:prevention & control; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D011753:Pyrones / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D024482:Vitamin K 2 / Q000494:pharmacology; D064417:Vitamin K Epoxide Reductases
D000925:Anticoagulants; D000933:Antifibrinolytic Agents; D004791:Enzyme Inhibitors; D005503:Food Additives; D011753:Pyrones; D024482:Vitamin K 2; C027493:dehydroacetic acid; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases