Transcript Vitamin K

Vitamin K
Dr. Amani A. Alrasheedi
Associated Professor
Nutrition and food Science
King Abdul Aziz University
History
• It was named from the Danish word koagulation,
which means “coagulation.”
• In the 1920s, Dam discovered that chicks fed a
low-fat and cholesterol-free diet became
hemorrhagic (bleed excessively) and that their
blood took a long time to clot.
• In 1943, Dam and Doisy had Nobel prize in
medicine for discovering the factor (vitamin K)
that corrected the problem and its role in blood
clotting.
Vitamin K
• Vitamin K was discovered as a result of
investigations into the cause of a bleeding
disorder (hemorrhagic disease) of cattle fed on
silage made from sweet clover and of chickens
fed on a fat-free diet.
• The missing factor in the diet of the chickens was
identified as vitamin K, whereas the problem in
the cattle was that the feed contained dicumarol,
an antagonist of the vitamin.
Chemical forms
All vitamin K active
compounds have a 2methyl 1,4naphthoquinone ring.
 Phylloquinone (K1):
Naturally occurring forms in
green plants.
 Menaquinones (K2):
Generally are synthesized by
human bacteria.
 Menadione (K3):
Synthetic, water soluble form
Complexed to improve
stability
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Vitamin K forms
• Three compounds have the biological activity of
vitamin K:
● Phylloquinone, the normal dietary source, found
in green leafy vegetables;
● Menaquinones, a family of related compounds
synthesized by intestinal bacteria, with differing
lengths of the side-chain;
● Menadiol and menadiol diacetate, synthetic
compounds that can be metabolized to
phylloquinone.
Sources
• Plants sources: mostly phylloquinone, accounts 90% of
intakes. all green leafy vegetables; the richest sources
are spring (collard) greens, spinach, and Brussels
sprouts. In addition, soybean, rapeseed, cottonseed,
and olive oils are relatively rich in vitamin K.
• Animal sources: a mixture of menaquinones. Found in
milk and milk products, meat, liver, fermented foods.
• GIT bacteria (colon): as source of menaquinones for
humans but not sufficient to meet the needs of health
children and adults.
• Exposure to light and heat can result in significant
vitamin K destruction.
Absorption, Transport and Storage
Phylloquinone:
Absorbed in small intestine (jejunum).
Its absorption occurs as part of micelles and thus
is enhanced by presence of dietary fats, bile
salts, and pancreatic juice.
 Menaquinones: (from GIT bacteria)
Absorbed in ileum and colon by passive diffusion.
The ability to absorb and use the bacterial vitamin
varies considerably from person to another.
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Absorption, Transport and Storage
In intestinal cell:
phylloquinones are incorporated into the chylomicron,
then enters lymphatic and circulatory system for
transport to liver and tissues.
Chylomicrons transport most phylloquinone.
 Chylomicron remnants deliver vitamin K to the liver.
 In liver:
Absorbed phylloquinone and menaquinone incorporated
into VLDL, and ultimately carried to extrahepatic
tissues in LDL and HDL.
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The dietary
vitamin K
pathway
absorption
Storage
Vitamin K is stored in several tissues.
 Phylloquinones are found in higher concentrations in the
liver, with lesser amounts in the heart, lungs, kidneys,
among other tissues.
Hepatic phylloquinone 2 - 20 ng/g liver.
 Menaquinone-4 (MK-4) found in many tissues
[pancreas, salivary glands, brain, and bone].
 Circulating plasma phylloquinones 0.15 -1.15 ng/mL.
 The body pool size of vitamin K [ 50 -100 μg ], is quite
low for a fat-soluble vitamin.
 Turnover of vitamin K is rapid, approximately once
every 2.5 hours
Metabolic functions of vitamin K
• Although it has been known since the 1920s
that vitamin K was required for blood clotting.
• It is the cofactor for the carboxylation of
glutamate residues in the postsynthetic
modification of proteins to form the unusual
amino acid γ-carboxyglutamate, abbreviated
to Gla.
Functions & mechanism of action
Necessary for the post-translational carboxylation
of glutamyl residues in specific proteins to form γcarboxyglutamate residues, which enable the protein
to bind Ca and interact with other compounds.
 These interactions are involving in:
Blood clotting (hemostasis)
Bone mineralization
(apoptosis, signal transduction, and growth control).
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Functions & mechanism of action
• Necessary for the post-translational carboxylation
of glytamyl residues in specific proteins to form ϒcarboxyglutamate residues, which enable the
protein to bind Ca and interact with other
compounds.
• These interactions are involving in:
• 1- blood clotting (hemostasis)
• 2- bone mineralization
• (apoptosis, single transduction, and growth
control)
Physiological Effects of Vitamin K
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Vitamin K serves as an
essential cofactor for a
carboxylase that catalyzes
carboxylation of glutamic
acid residues on vitamin Kdependent proteins.
These proteins are involved
in:
1) Coagulation
2) Bone Mineralization
3) Cell growth
Vitamin K and Blood Clotting
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Vitamin K–dependent post-translational
carboxylation of glutamyl residues forms γcarboxyglutamate on four major proteins required
for coagulation of blood.
These 4 proteins [factors II (prothrombin), VII,
IX, and X] for coagulation.
In addition, proteins C, S, and Z, also require
vitamin K for carboxylation, but to inhibit the
coagulation process (anticoagulants).
Vitamin K Dependent Proteins
Factor II (prothrombin)
 Factor VII (proconvertin)
 Factor IX (thromboplastin component)
 Factor X (Stuart factor)
 Protein C & protein S
 Protein Z
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Overview of Blood Clotting
For blood to clot,
Fibrinogen (soluble protein) ------- fibrin (insoluble
fiber
Thrombin
network)
 Fibrin molecules ----- fibrin polymer (insoluble clot)
fibrin stabilizing factors (XIII)
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In extrinsic pathway:
 factor VII -------------- VIIa (carboxylated vit-K dependent)
thrombin & Xa and XIIa
Factors IX, X ------------ IXa, Xa
Factor VIIa + Ca
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In intrinsic pathway:
Prothrombin ---------- thrombin
actor Xa-vitamin K
fibrinogen -------- fibrin (clot formation)
Clotting Cascade
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Proteins C, S, and Z, also identified as vitamin K–dependent
carboxylated proteins.
The function of proteins C & S appear to inhibit the blood-clotting
process (anticoagulant).
p-C + thrombomodulin + Ca ---- protein-Ca
Thrombin
VIIIa , Va --------- inactive VIII, V (disrupt clotting)
Protein-Ca + p-S
Protein S found in blood and bone.
protein Z function is unknown
C, S are important to maintaining the balance between bleeding and
clotting
Protein C in its activated form has a direct anti-inflammatory function
Protein S are widely distributed in tissues and are thought it has roles
in protecting the integrity of cellular function (particularly in brain)
Vitamin K and bone & nonosseous
tissue proteins
Bone, cartilage and dentine have 2 vit K–dependent proteins:
osteocalcin, bone Gla protein (BGP)
and matrix Gla protein (MGP).
Synthesis of both proteins stimulated by calcitriol & retinoic acid.
Osteocalcin is secreted by osteoblasts during bone formation.
Osteocalcin comprises 15-20% of noncollagen protein in bone.
With vitamin K–dependent carboxylation, the three Gla residues on
osteocalcin facilitate the binding of calcium ions in the
hydroxyapatite lattice.
 Osteocalcin appears to be involved in bone remodeling or
calcium mobilization.
 MGP is found in bone, dentine, and cartilage and is associated
with the organic matrix and mobilization of bone calcium. able
to prevent the process of calcification of arteries and cartilage in
living animals.
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Vitamin K Cycle
Reductase
Vitamin KH2
Vitamin K
Warfarin Inhibits
Epoxide
Reductase
Vitamin K Epoxide
Glutamic Acid
Vitamin K Dependent
Carboxylase
Gamma Carboxy
Glutamic Acid
Interactions with other nutrients
Vitamins A and E are antagonize vitamin K.
Excess vitamin A interfere with vitamin K absorption.
Vitamin E’s possibly inhibit vitamin K absorption,
function, and metabolism by blocking the regeneration
of reduced form of vitamin K.
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Interrelationship among vitamins K, D & A
because their relationship to calcium.
Metabolism and Excretion
Phylloquinone is completely metabolized to a
variety of metabolites before being excreted,
which degraded much more slowly than
menaquinone.
 Most of phylloquinone metabolites excreted
primarily in feces by the bile, and some excreted
in urine.
 little is known about metabolism and excretion
of menaquinone, which are excreted in bile and
thus in feces) and in urine
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Physiological effects of vitamin K
• Post- translational carboxylatio of glutamyl
residues.
• Vitamin K dependent proteins are involved in:
• 1- coagulation
• 2- bone mineralization
• 3- cell growth.
Vitamin K and blood clotting
• Vitamin K- dependent post- translational
carboxylation of glutamyl residues forms ϒcarboxyglutamate on four major proteins
required for coagulation of blood.
• These four proteins (factors 2 (prothrombin) 7,
9 and 10 for coagulation.
• In addition, proteins C, S and Z also require
vitamin K for carboxylation, but to inhibit the
coagulation process (anticoagulants).
Adequate intake
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Adequate intake (AI):
30 µg for children (1-3 years)
55 µg for children (4-8 years)
60 µg for children (9-13 years)
75 µg for adolescents (14-18 years)
120 µg for adult men
90 µg for adult women
Deficiency
• A deficiency of vitamin K is unlikely in healthy adults.
• Risk population groups:
• Newborn infants (limited vitamin K in milk, low vitamin
stores).
• People treaded with antibiotics.
• People consuming vitamin K poor diet + prolonged
antibiotic drug therapy.
• People with fat malabsorptive disorders (obstructive
jaundice, diarrhea, chronic pancreatitis & liver disease).
Toxicity
• Ingestion of large amounts of vitamin K (both
forms) not causing any symptoms of toxicity.
• Large amounts of synthetic product
(menadione) can cause liver damage.
• in infants menadione supplementation
caused hemolytic anemia and severe jaundice.
Assessment of nutrient status
Plasma phylloquinone conc. reflect recent intake
of the vitamin.
 Routinely measured whole blood clotting times
and prothrombin time.
normal prothrombin time 11- 14 sec.
> 25 sec. (bleeding)
 Measure undercarboxylated vitamin K–
dependent proteins
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