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-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)

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 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]

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]

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 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]

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

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 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]

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]

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]

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

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

Works Cited: 1.Alam, P., et al. (2016). Vitamin K3 inhibits protein aggregation: Implication in the treatment of amyloid diseases. SciReports., 6, doi: /srep Booth, S.L. & Saltzman, E. (2001). Vitamin K: Structure and Function. Retrieved from 3.Bungard, T.J., Yakiwchuk E., Foisy, M., Brocklebant, C. (2011). Drug interactions involving warfarin: practical tool and practical management tips. CPJ/RPC.,144: Dowd, P., et al. (1995). Vitamin K and energy transduction: A base strength amplification mechanism. Science., 22: Gast, G.C.M., et al. (2009). A high menaquinone intake reduces the incidence of coronary heart disease. NMCD., 19(7), 504–510. doi: /j.numecd Hamidi, M.S., et al. (2013). Vitamin K and Bone Health. Retrieved from 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), 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– 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: Oldenburg, J. et al. (2008). The vitamin K cycle. Vitam Horm., 78: Shea, M.K. & Booth, S.L. (2008). Update on the role of vitamin K in skeletal health. Nutr Rev., 66(10): doi: /j 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: Shearer, M.J. (1992). Vitamin K metabolism and nutrition. Blood Rev., 6: Shearer, M.J., McBurney, A. & Barkhan, P. (1974). Studies on the absorption and metabolism of phylloquinone (vitamin K 1 ) in man. Vit. Horm., 32: 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: /j.thromres