Download The Biology of Vitamin K

The Biology of Vitamin
PHM 142
Tuesday September 14
Samantha Koenig, Grace Liang,
Yunjin (Jenny) Sun, Yunlu (Joella) Wang
PHM142 Fall 2016
Instructor: Dr. Jeffrey Henderson
Vitamin K
● Family of compounds containing
the parent compound: 2-methyl1,4-naphthoquinone (aka
menadione)
Phylloquinone (K1)
- Ingested via green leafy vegetables
Menaquinones (MK-n) (K2)
- Bacterial synthesis
● Fat soluble
● Important cofactor for blood
coagulation and bone metabolism
by regulating Ca2+ distribution [2]
Menadione (K3)
- Synthetically produced
(Booth & Saltzman, 2001)
Absorption, Transportation & Excretion
● Absorption occurs through the small
intestine by solubilizing vitamin K in bile
salts [9]
● Transportation out of the small intestine
uses chylomicrons
● Vitamin K is stored in the liver and
excreted out as in either bile or urine
[15-17]
Blood Coagulation
●
Vitamin K is important cofactor in the coagulation
cascade  helps produce carboxyglumatic acid which
is critical for biologic activity of enzyme
●
Effects clotting factors prothrombin (II), Factor VII, IX
and X [4]
Vitamin K Cycle
●
Vitamin K-dependent carboxylase changes
glutamic acid (Glu) on inactive enzyme to
carboxyglutamic acid (Gla)
●
Simultaneously, Vitamin KH2 is oxidized to
Vitamin K epoxide
●
Vitamin K epoxide is recycled through a two
step reduction process
●
Recycling is important to maintain active
biological function [12,13]
Bone Metabolism
● Serves as a cofactor for the carboxylation of Glu → Gla residues in vitamin Kdependant proteins in bone (same process as mentioned previously)
● Three vitamin K-dependant proteins in bone: osteocalcin, matrix Gla protein,
Protein S [6,10]
● Low circulating vitamin K1, K2, low intake in K1 and high serum levels of
uncarboxylated osteocalcin associated with higher risks of hip fractures [14]
Drug Interactions
1: Warfarin
2: Broad spectrum antibiotics (ex. cephalosporin and salicylates)
3: Cholesterol-lowering medication
Warfarin
● Anticoagulant
● It antagonizes vitamin K recycling, it does not directly antagonize vitamin K1
action
- Warfarin inhibits the enzyme vitamin K epoxide
and quinone reductase which convert oxidized
vitamin K to its reduced form
- Thus, warfarin interferes with the enzyme that
recycles vitamin K and thereby indirectly
impacts vitamin K [8]
Why is this important?
● Reduced vitamin K is crucial for hepatic production of the active vitamin K
dependent clotting factors II, VII, IX, X which are involved in the blood clotting
cascade
● As a result, warfarin decreases the levels and availability of vitamin K
dependent clotting factors by preventing the oxidized vitamin K from returning
to its reduced form.
● Thus, warfarin acts as an anticoagulant since the clotting factors are no
longer available [8]
To reverse this effect
In case of surgery or excessive bleeding, International Normalized Ratio >10
1) Oral administration of phytonadione (exogenous vitamin K):
- This provides fresh (reduced) vitamin K thereby allowing the hepatic
production of vitamin K dependent clotting factors → increase ability for blood
clotting
2) IV administration:
- For immediate results
- Not preferred due to complications, such as anaphylaxis [8]
Broad Spectrum Antibiotics
Ex. cephalosporin and salicylates
- Interfere with production of vitamin K by intestinal bacteria since these antibiotics
decrease intestinal flora [3]
- Lower vitamin K absorption
Cholesterol-lowering Medications
Ex. cholestyramine, colestipol
- Affect absorption of fat soluble vitamins such as vitamin K [7]
Deficiency
● Average diets are usually not lacking in
vitamin K [5]
● Some populations, such as newborn
infants, patients with liver damage or
recently had abdominal surgeries are at
an increased risk of deficiency [18]
Recommended dietary intake of vitamin K
Deficiency
● Deficiency in vitamin K1 can result in
- Impaired blood clotting
- Anemia and easy bruising
- Easy bleeding
● Deficiency in vitamin K2 are associated with
- Osteoporosis
- Coronary heart disease [5]
Toxicity
● No known toxicity is associated with high doses of the Vitamin K1 or K2
- No toxicities have been reported as being associated with excessive
intake of natural vitamin K
● Vitamin K3 has a finite toxicity
- Large doses may cause hemolytic anemia, chest constriction and
flushing [11]
Recent Discovery
● Studies showed that vitamin K3
inhibits protein misfolding and
aggregation
● Amyloid fibrillation of protein have
been associated with several
human diseases such as
Alzheimer's, Parkinson's and
Huntington's disease [1]
Summary
● Vitamin K1 comes from dietary intake, vitamin K2 produced by bacteria
● Stored in liver and distributed throughout blood
● Functions as cofactor in blood coagulation and bone metabolism
● Anticoagulant drugs (ex: warfarin) targets vitamin K epoxide and quinone
reductase and halts the recycling process of the vitamin K cycle
● Deficiency not common in average adults and no known toxicity levels for
vitamin K1 & K2
Summary cont.
●Warfarin acts as an anticoagulant since the clotting factors are no longer available
●Deficiency in vitamin K1 can result in
- Impaired blood clotting
- Anemia and easy bruising
- Easy bleeding
●Deficiency in vitamin K2 are associated with
- Osteoporosis
- Coronary heart disease
Works Cited:
1. Alam, P., et al. (2016). Vitamin K3 inhibits protein aggregation: Implication in the treatment of amyloid diseases.
SciReports., 6, 26759. doi:10.1038/srep26759
2. Booth, S.L. & Saltzman, E. (2001). Vitamin K: Structure and Function. Retrieved from
http://onlinelibrary.wiley.com/doi/10.1038/npg.els.0001411/full
3. Bungard, T.J., Yakiwchuk E., Foisy, M., Brocklebant, C. (2011). Drug interactions involving warfarin: practical tool and
practical management tips. CPJ/RPC.,144:21-34.
4. Dowd, P., et al. (1995). Vitamin K and energy transduction: A base strength amplification mechanism. Science., 22:16841691.
5. Gast, G.C.M., et al. (2009). A high menaquinone intake reduces the incidence of coronary heart disease. NMCD., 19(7),
504–510. doi:10.1016/j.numecd.2008.10.004
6. Hamidi, M.S., et al. (2013). Vitamin K and Bone Health. Retrieved from
http://journals1.scholarsportal.info.myaccess.library.utoronto.ca/details/10946950/v16i0004/409_vkabh.xml
7. Hendler, S.S. & Rorvik, D.R. (2001) PDR for Nutritional Supplements. Montvale. Medical Economics Company Inc.
8. Kalus, J.S. (2013). New approaches to reversing oral anticoagulant therapy. American Journal of Health System
Pharmacy, 70(12), 512-513.
9. Kohlmeier, M. (1996). Transport of vitamin K to bone in Humans. J. Nutr., 126: 1192S-6S.
Works Cited (continued):
10. Luo, G., et al. (1997). Spontaneous calcification of arteries and cartilage in mice lacking matrix Gla protein. Nature., 386:
78–81.
11. McKee, M. B. et al. (2008). Herb, nutrient, and drug interactions : clinical implications and therapeutic strategies (4th
ed.). St. Louis, Mo.
12. Oldenburg, J. et al. (2006). Vitamin K epoxide reductase complex subunit 1 (VKORC1): The key protein of the vitamin K
cycle. Antioxid Redox Signal., 8: 347-353.
13. Oldenburg, J. et al. (2008). The vitamin K cycle. Vitam Horm., 78: 35-62.
14. Shea, M.K. & Booth, S.L. (2008). Update on the role of vitamin K in skeletal health. Nutr Rev., 66(10):549-557.
doi:10.1111/j.1753-4887.2008.00106.x
15. Shearer, M.J., Barkhan, P. & Webster, G.R. (1970). Absorption and excretion of an oral dose of tritiated vitamin K1 in
man. Br. J. Haematol., 18:297-308.
16. Shearer, M.J. (1992). Vitamin K metabolism and nutrition. Blood Rev., 6: 92-104.
17. Shearer, M.J., McBurney, A. & Barkhan, P. (1974). Studies on the absorption and metabolism of phylloquinone (vitamin
K1) in man. Vit. Horm., 32: 513-42.
18. Wallin, R., Schurgers, L., & Wajih, N. (2008). Effects of the blood coagulation vitamin K as an inhibitor of arterial
calcification. Thrombosis Research., 122(3), 411–417. doi:10.1016/j.thromres.2007.12.005