1. 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

2. Vitamin K ●Family of compounds containing the parent compound: 2-methyl- 1,4-naphthoquinone (aka menadione) ●Fat soluble ●Important cofactor for blood coagulation and bone metabolism by regulating Ca 2+ distribution [2] Phylloquinone (K1) - Ingested via green leafy vegetables Menaquinones (MK-n) (K2) - Bacterial synthesis Menadione (K3) - Synthetically produced (Booth & Saltzman, 2001)

3. 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]

4. 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]

5. Vitamin K Cycle ●Vitamin K-dependent carboxylase changes glutamic acid (Glu) on inactive enzyme to carboxyglutamic acid (Gla) ●Simultaneously, Vitamin KH 2 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]

6. Bone Metabolism ●Serves as a cofactor for the carboxylation of Glu → Gla residues in vitamin K- dependant 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 K 1, K 2, low intake in K 1 and high serum levels of uncarboxylated osteocalcin associated with higher risks of hip fractures [14]

7. Drug Interactions 1: Warfarin 2: Broad spectrum antibiotics (ex. cephalosporin and salicylates) 3: Cholesterol-lowering medication

8. Warfarin ●Anticoagulant ●It antagonizes vitamin K recycling, it does not directly antagonize vitamin K 1 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]

9. 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]

10. 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]

11. 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 Ex. cholestyramine, colestipol - Affect absorption of fat soluble vitamins such as vitamin K [7] Cholesterol-lowering Medications

12. 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

13. Deficiency ●Deficiency in vitamin K 1 can result in  Impaired blood clotting  Anemia and easy bruising  Easy bleeding ●Deficiency in vitamin K 2 are associated with  Osteoporosis  Coronary heart disease [5]

14. Toxicity ●No known toxicity is associated with high doses of the Vitamin K 1 or K 2  No toxicities have been reported as being associated with excessive intake of natural vitamin K ●Vitamin K 3 has a finite toxicity  Large doses may cause hemolytic anemia, chest constriction and flushing [11]

15. Recent Discovery ●Studies showed that vitamin K 3 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]

16. Summary ●Vitamin K 1 comes from dietary intake, vitamin K 2 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 K 1 & K 2

17. Summary cont. ●Warfarin acts as an anticoagulant since the clotting factors are no longer available ●Deficiency in vitamin K 1 can result in  Impaired blood clotting  Anemia and easy bruising  Easy bleeding ●Deficiency in vitamin K 2 are associated with  Osteoporosis  Coronary heart disease

18. 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., 22:1684- 1691. 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.

19. 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 K 1 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 K 1 ) 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