Vitamin K as a Ligand of Steroid and Xenobiotic Receptor pp. 209-216
Authors: (Kotaro Azuma, Kuniko Horie-Inoue, Yasuyoshi Ouchi, Satoshi Inoue, University of Tokyo and Saitama Medical University, Japan)
Abstract: Vitamin K is a fat-soluble vitamin essential for blood coagulation. Natural vitamin K includes vitamin K1 (phylloquinone), present mainly in vegetables, and vitamin K2 (menaquinone), which is synthesized by microorganisms and is present in food such as natto (fermented soy beans). Vitamin K1 is converted to vitamin K2, the functionally active form, in the body . Vitamin K was shown to play an essential role in the hepatocytes by maintaining the activity of coagulation factors II, VII, IX, and X and of anticoagulants, protein C, and protein S. Recently, extrahepatic actions of vitamin K have also been reported. The administration of vitamin K was shown to prevent bone fracture [2, 3], and this led to its clinical application in cases of osteoporosis in East Asian countries. Epidemiological studies have shown that the lack of vitamin K causes osteoarthritis  and imposes a risk of coronary artery disease . Some clinical studies have suggested its antitumor activity in cases of hepatocellular carcinoma [6-8] and other cancers . Until recently, vitamin K was primarily known as a co-enzyme of γ-glutamyl carboxylase (GGCX), which converts glutamic acid (Glu) to γ-carboxyglutamic acid (Gla) during the post-transcriptional modification of proteins. During this reaction, vitamin K is oxidized from vitamin K hydroquinone to vitamin K epoxide. Thus far, the following 15 proteins are known to be the substrates of GGCX: coagulation factors II, VII, IX, and X; protein C; protein S; growth arrest specific-6 (Gas6) ; osteocalcin (also known as bone Gla protein [BGP]) ; matrix Gla protein (MGP) ; periostin ; Ig-H3 ; proline-rich Gla proteins 1 and 2 ; and transmembrane Gla proteins 3 and 4 . Warfarin, which is clinically used as an anticoagulation drug, inhibits the activity of vitamin K epoxide reductase (VKOR). The lack of VKOR activity renders the GGCX-oxidized vitamin K useless, resulting in a decrease in the GGCX activity.
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