The role of dietary vitamin K in the management of oral vitamin K antagonists

Scheme showing the vitamin K epoxide cycle in the absence (A) and presence (B) of warfarin. A shows the linkage of the post-translational conversion of peptide-bound glutamic acid (Glu) to γ-carboxy glutamic acid (Gla) residues to the metabolic recycling of vitamin K by a pathway known as the vitamin K-epoxide cycle. Enzyme activities shown are (1) γ-glutamyl carboxylase; (2) vitamin K epoxide reductase (VKOR) and (3) NAD(P)H-dependent quinone reductase(s). The active cofactor form of vitamin K required by the γ-glutamyl carboxylase is the reduced form vitamin K quinol (KH₂). During γ-glutamyl carboxylation KH₂ becomes oxidised to vitamin K epoxide (KO) which in turn undergoes reductive recycling, first to the vitamin K quinone (K) and then to KH₂. Only the VKOR enzyme can carry out the reduction of KO to K and under usual physiological conditions both VKOR and NAD(P)H-dependent quinone reductases can carry out the reduction of K to KH₂. B shows the metabolic inhibition and consequences of a vitamin K antagonist such as warfarin. These drugs block the activity of the VKOR (2) leading to an accumulation of KO in the cell. Given a sufficient supply of vitamin K (e.g. from the diet) an alternative hepatic quinone reductase activity (3) can bypass the warfarin inhibition of the VKOR to provide the KH₂ substrate for the carboxylase enzyme and overcome the inhibitory action of warfarin, even under extreme blockade. The scheme also shows that in the absence of warfarin, the carboxylated substrates (Gla proteins) are secreted into the circulation (A) whereas in the presence of warfarin, species of undercarboxylated forms called PIVKAS are also secreted into the circulation (B). This Figure originally published in “Vitamins in the prevention of human diseases/Wolfgang Herrmann, Rima Obeid/De Gruyter, Berlin 2011” reproduced with kind permission of De Gruyter.