1. Absorption, transport and metabolism of vitamin K
Domina Petric, MD

2. Absorption of vitamin K
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

3. Micellar solubilization
The vitamers K are absorbed from the intestine into the lymphatic circulation by processes that first require that these hydrophobic substances be dispersed in the aqueous lumen of the gut via the formation of mixed micelles, in which they are dissolved.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

4. Micellar solubilization
Vitamin K absorption depends on normal pancreatic and biliary function.
Conditions resulting in impaired lumenal micelle formation (dietary mineral oil, pancreatic exocrine dysfunction, bile stasis) impair the enteric absorption of vitamin K.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

5. Active transport of phylloquinone
Phylloquinone is absorbed by an energy-dependent process from the proximal small intestine.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

6. Other vitamers absorption
The menaquinones and menadione are absorbed strictly via non carrier-mediated passive diffusion, the rates of which are affected by the micellar contents of lipids and bile salts.
This kind of passive absorption has been found to occur in the distal part of the small intestine as well as in the colon.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

7. Transport of vitamin K II.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

8. Absorbed vitamin K transferred to lipoproteins
On absorption, vitamin K is transported in the lymph in association with chylomicra, whereby it is transported to the liver.
Vitamin K is rapidly taken up by the liver, but it has a relatively short half-life there (about 17 hours) before it is transferred to very low-density lipoproteins (VLDLs) and low-density lipoproteins (LDLs).
VLDLs and LDLs carry it in the plasma.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

9. Absorbed vitamin K transferred to lipoproteins
No specific carriers have been identified for any of the vitamers K.
Plasma levels of phylloquinone are correlated with those of triglycerides and α-tocopherol: 0.1–0.7 ng/ml.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

10. Tissue distribution
When administered as either phylloquinone or menaquinone, vitamin K is rapidly taken up by the liver, which is the site of synthesis of the vitamin K-dependent coagulation proteins.
Little menadione is taken up by the liver, instead, it is distributed widely to other tissues.
Hepatic storage of vitamin K has little long term significance: vitamin K is rapidly removed from liver and rapidly excreted.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

11. Tissue distribution
Adrenal glands, lungs, bone marrow, kidneys and lymph nodes tend to concentrate vitamin K.
The transplacental movement of vitamin K is poor: the vitamin is frequently not detectable in the cord blood from mothers with normal plasma levels.
Newborn infants are susceptible to hemorrhage.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

12. Tissue distribution
In each organ, vitamin K is found localized primarily in cellular membranes (endoplasmic reticulum, mitochondria).
Under conditions of low vitamin K intake, the vitamin appears to be depleted from membranes more slowly than from cytosol.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

13. Metabolism of vitamin K
III.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

14. Side-chain modification
Dealkylation
Alkylation
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

15. Dealkylation
The metabolic dealkylation of the phylloquinone side chain (converting it to menadione), followed by its realkylation to the menaquinones is greatest when phylloquinone is taken orally.
This dealkylation is performed during intestinal absorption and/or by gut microbes.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

16. Alkylation The alkylation of menadione does occur in vivo.
The main product of the alkylation of menadione is MK-4.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

17. Redox cycling
Vitamin K is subject to a cycle of oxidation and reduction that is coupled to the carboxylation of peptidyl glutamyl residues to produce various functional γ-carboxylated proteins.
The redox cycling of vitamin K occurs in three steps.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

18. Oxidation of dihydroxyvitamin K to vitamin K 2,3-epoxide1.
Oxidation of dihydroxyvitamin K to vitamin K 2,3-epoxide
The production of the 2,3-epoxide, also called vitamin K epoxide or vitamin K oxide, is catalyzed by vitamin K γ-glutamyl carboxylase.
Carboxylase is a 94 kD protein located in the endoplasmic reticulum and Golgi apparatus.
Vitamin K 2,3-epoxide comprises about 10% of the total vitamin K in the normal liver.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

19. Reduction of the 2,3-epoxide to vitamin K quinone2.
Reduction of the 2,3-epoxide to vitamin K quinone
This step is catalyzed by vitamin K epoxide reductase, a dithiol-dependent, microsomal enzyme inhibited by the coumarin type anticoagulants.
Genetic variability in the vitamin K epoxide reductase is thought to account for the variability observed among patients in their responses to warfarin therapy.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

20. Reduction of the quinone to the active dihydroxyvitamin K3.
Reduction of the quinone to the active dihydroxyvitamin K
This final reductive step can be catalyzed in two ways:
By vitamin K quinine reductase, a dithiol dependent microsomal enzyme that is inhibited by the coumarin-type anticoagulants.
By DT-diaphorase, a microsomal flavoprotein that uses NAD(P)H as a source of reducing equivalents. Unlike the dithiol dependent enzyme, it is relatively insensitive to coumarin inhibition, such that reduction of vitamin K quinone persists in anticoagulant treated individuals.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

21. Catabolism
IV.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

22. Menadione
Menaquinone is rapidly metabolized and excreted, leaving only a relatively minor portion to be converted to MK-4.
It is excreted primarily in the urine (about 70% of a physiological dose may be lost within 24 hours) as the phosphate, sulfate or glucuronide of menadiol.
It is also excreted in the bile as the glucuronide.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

23. Extensive side-chain conversion occurs.
Menaquinone
Extensive side-chain conversion occurs.
Its catabolism appears to be much slower than that of menadione.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

24. Phylloquinone
The total body pool of phylloquinone, about 100 mg in an adult, appears to turnover in about 1.5 days.
This involves the vitamer undergoing oxidative shortening of the side chain to 5- or 7-carbon carboxylic acids and a variety of other, more extensively degraded metabolites.
A fifth of phylloquinone is excreted in the urine.
The primary route of excretion of these metabolites is the feces, which contain glucuronic acid conjugates excreted via the bile.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

25. Vitamin K antagonists V.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

26. Vitamin K antagonists
The coumarin-type anticoagulants block the thiol dependent regeneration of the reduced forms of the vitamin, resulting in the accumulation of the 2,3-epoxide.
The attendant loss of dihydroquinone results in a loss of protein γ-carboxylation and, consequently, the loss of active Gla-proteins.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

27. Literature
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc
November 16, 2018