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Vitamin K: metabolism, physiopathology, implication in the inter- and intra-individual variability in the response to the vitamin K antagonists Volume 12, issue 6, Novembre-Décembre 2006

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Laboratoire d’hématologie, groupe hospitalier Charles-Foix – Jean-Rostand, 7 avenue de la République, 94205 Ivry-sur-Seine Cedex et Hématologie, Faculté de Pharmacie, Paris V, 4 av. de l’Observatoire, 75006 Paris

Vitamin K exists in different forms: vitamin K1 (phylloquinone) is preferentially found in green leafy vegetables, vitamin K2 (menaquinones) is from animal source, and vitamin K3, (menadione) is a chemically synthesized derivative. In this review, recent advances in understanding the vitamin K cycle and its implication in the vitamin-K dependent (VKD) protein functions are discussed. The quinone forms of vitamin K contained in the diet require reduction to serve as a co-substrate for the γ-carboxylation of VKD proteins. During this step, glutamyl residues (Glus) of VKD proteins are converted to Glas by a γ-glutamyl carboxylase, and the vitamin K hydroquinone is oxidized to a vitamin K epoxide product. The γ-carboxylase has a high-affinity site that selectively binds to VKD proteins through their propeptide, and a site for reduced vitamin K. Before it can be reused, the vitamin K epoxide must be converted back to reduced vitamin K by the vitamin K epoxide reductase (VKOR), defining the vitamin K cycle. The post-translational γ-carboxylation is required for the VKD protein activity. These proteins are involved in a broad range of physiological processes, including haemostasis (coagulation factors II, VII, IX, X, proteins C, S, Z), but also bone metabolism and osteoporosis (osteocalcin and matrix Gla protein), inhibition of artery calcification (matrix Gla protein), growth control (Gas-6), or signal transduction. The amount of vitamin K in the diet is often limiting for the carboxylation reaction. Vitamin K antagonists (VKA) inhibit VKOR and cause decreased γ-carboxylase catalysis of VKD proteins. Since decades, it is well known that the maintenance dose of VKA is influenced by different acquired factors including demographic data (age, sex, BMI…), dietary vitamin K intake, comorbid conditions, acute illnesses, co-medications. About ten years ago, allelic variants of the gene coding for cytochrome P450 isoform 2C9 (CYP2C9) were shown to increase sensitivity to coumarinic derivatives. More recently, haplotypes in the VKORC1 gene have been found to affect VKA dose response. More than 50 per cent of variability is now explained by the patient’s age and his genetic polymorphisms. In the future, new warfarin dosing regimens including patient characteristics, CYP2C9 and VKORC1 genetic polymorphisms might be proposed at the onset of warfarin treatment.