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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