Lipid-Soluble Vitamins

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Lipid-Soluble Vitamins

• Medical Biochemistry
• Lecture 56

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Organization of Vitamin Information

• Structure of the vitamin
• Function of the vitamin
• Signs symptoms of deficiency
• Sources circumstances leading to deficiency
• Signs and symptoms of toxicity

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History of Vitamin ResearchVitamin A vs.
Vitamin B

• Lipid extraction A
• Water extraction B
• Vitamins A, D, and E
• Vitamin K
• B was complex.

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Fat-soluble Vitamin Deficiencies in Children with
Cholestasis

• Vitamin K (prothrombin time lt 80) 26
• Vitamin A (lt 30 µg/dL) 35
• Vitamin E (mgE/g lipid lt 0.6) 66
• Vitamin D (25 - OH lt 14 µg/dL 66
• N 23

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Isoprene
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Retinol (Vitamin A)
CH2OH
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ß-carotene
ß-carotene is Converted to Vitamin A
O2 Bile salts
ß-carotene Dioxygenase
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Retinal is Reduced to Retinol
NADPH (NADH) H
Retinaldehyde Reductase
NADP (NAD)
CH2OH
Retinol
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Retinal can be Oxidized to Retinoic Acid
NAD, FAD
OH
C
O
Retinoic acid (all-trans)
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Role of 11-cis-retinal in the Visual Cycle
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Binding Proteins Receptors for the Various
Forms of Vitamin A

• Retinol-binding protein (RBP) plasma transport
• Cellular retinoid-binding proteins
• Cellular retinol binding proteinsCRBP I CRBP
  II (Intestinal absorption)
• Cellular retinoic acid binding proteins CRABP I
  CRABP II (Embryogenesis)

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Binding Proteins Receptors for the Various
Forms of Vitamin A (cont.)

• Nuclear retinoid receptors (transcription
  factors)
• Retinoic acid receptors
• RAR? RARß RAR? and RXR
• Specific DNA nucleotide sequencesRetinoic Acid
  Response Elements
• RARE
• RXRE

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Cells Dependent on Vitamin A

• Skin
• Cornea
• Trachea
• Immunocytes

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Bitots Spots
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Bitots Spots
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Vitamin A in Food Carotene Vitamin A Esters
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Hypervitaminosis A

• Vitamin A (not carotenoids)
• Liver damage
• Hemorrhage
• Coma
• Death

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Vitamin A Teratogenesis

• Associated with gt 20 rate of spontaneous
  abortions and birth defects
• 13-cis-retinoic acid
• During first trimester
• Accutane

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Anti-carcinogenic Properties of Vitamin A

• Epidemiologic studies
• Colon
• Skin, breast, liver, prostate, lung
• Not replicated in basal diet separately or in
  combination
• Other compounds in fruits vegetables?
• Mechanism?
• Oxygen radical trap
• A complements properties of E

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The Role of Vitamin D

• Maintains plasma calcium phosphorous
  concentrations
• Supports cellular processes, neuromuscular
  function, bone ossification
• Enhances calcium phosphorous absorption from
  small intestine mobilization from bone

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Structure of Vitamin D
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Vitamin D Metabolism
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Mechanism of Vitamin D

• Interactions with nuclear receptor in target
  tissues
• More rapid actions through
• Intracellular calcium
• Phosphatidyl inositol
• Cyclic GTP

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Bone Mineral Content in Children w/ Cholestasis
Changes in Bone Mineral Content
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Bowed Legs of Rickets
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Rachitic Rosary
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Toxicity of Vitamin D

• War-time supplementation
• 2,000 IU 50 - 100 more
• Nutritional deprivation
• Lack of sunlight
• Epidemic of calcimia
• Some permanent brain damage
• Resultant laws in Europe

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Vitamin ETocopherol
CH3
O
CH3
CH3
CH3
HO
(CH2 - CH2 - CH2 - CH)3 - CH3
CH3
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Role of Vitamin E

• Lipid peroxyl radical chain
• Biologic activities
• Correlates with anti-oxidant activities

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Sources and Absorption of Vitamin E

• Vegetable oils
• Bile salts
• Pancreatic secretions
• Mixed micelles
• Chylomicrons

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Progression of Neurologic Symptoms of Vitamin E
Deficiency
19 - 25 of patients
25 - 75 of patients
75 - 100 of patients
Hypoflexia or Areflexia
Truncal Ataxia
Limb Ataxia
Peripheral Neuropathy
Ophthalmoplegia
0 2 4 6 8 10 12 14 16
Age intervals, Year
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Roles of Carboxyglutamate
and Vitamin K

• Factors X, IX, and VII and thrombin contain a
  unique modified glutamate residue -
  carboxyglutamate (Gla).
• Gla residues result from post-translational
  modifications of the newly synthesized factors in
  the liver endoplasmic reticulum by a vitamin
  K-dependent carboxylase

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Vitamin K - dependent Carboxylase
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Chelation of Calcium
Ca2
O
O
-O
O-
C
C
CH
CH2
C
CH
N H
O
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Roles of Calcium and Carboxyglutamate

• Gla is a high affinity calcium chelator.
• Complex of calcium with the Gla-factors allow
  specific interactions with acidic membrane lipids
  that ultimately lead to the correct tertiary and
  quaternary protein structures recognized by other
  proteins in the pathway.

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Structures of the Coumarin Drugs (Vitamin K
analogs)
DICOUMAROL
VITAMIN K
WARFARIN
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Dicoumarol / Warfarin

• Coumarin (anticoagulate post- stent) and Warfarin
  (rat poison) are both analogs of Vitamin K.
• They inhibit formation of the Gla residues of
  prothrombin and Factors VII, IX and X.
• The lack of Gla residues, and hence binding of
  calcium, inhibits coagulation.

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Hemorrhagic Disease of the Newborn

• Intrauterine vitamin K deficiency
• Sterile intrauterine gut
• Why/how would Mother Nature let this happen?

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