Soluble Fat Vitamins 3
Vitamins E and K
NDFS 435
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Objectives
Discuss vitamin E and K forms, digestion,
transport and storage
Learn vitamin Es antioxidant mechanism
Learn the vitamin K cycle
Explore some clinical applications for E and
K
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Vitamin E History 1
1922 Evans and Bishop, UC Berkeley
Rat diet made with rancid lard
Female rats conceived, but could not complete the
pregnancy.
Recognized that something in the lard was
necessary for pregnancy.
Named vitamin E
Chemical name given by a Greek professor
Tocopher = to bring forth in childbirth
-ol = oil
Tocopherol
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Vitamin E History 2
1930s 1960s
Vitamin E deficiency effects determined in
many animal species
Many different effects
Reasons unclear at that time
Unreliable literature would compile the animal
results and imply that vitamin E deficiency in
humans had the same results
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Vitamin E History 3
1960s
One group said that vitamin E would prevent
heart disease
Several controlled studies followed
No effect was found on lowering serum cholesterol
Papers stated that vitamin E had no effect on heart disease
Lowering serum cholesterol was the only risk factor
identified at this time
Late 1960s
Antioxidant properties of vitamin E postulated
New era began
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R3
R2
8
7
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HO
O
1
5
R1
Tocol s
CH 3
2
3
R1 or R2
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CH3
R1 = CH2(CH2- CH2-CH- CH2)3H
Tocot rie nols
CH3
R2 = CH2(CH2-CH=C-CH2)3H
Methyl Positions
Tocol
Tocotr ienol
5, 7, 8
- (al pha)
5, 8
- ( beta)
7, 8
- (gam ma)
8
- (delt a)
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Chiral groups
Chiral groups
determine the
isomers
Nature
Synthesis
Synthesis of alphatocopherol results in
a racemic mixture of
all 8 isomers. Nature
only makes the RRR
isomer.
Only alpha-tocopherol has been shown to reverse
an induced vitamin E deficiency in humans.
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Recommendations
1989 RDA: RRR--tocopherol equivalents
Men: 10 mg
Women: 8 mg
Included the 8 naturally occurring tocopherols
2000 RDA: -tocopherol (not equivalents)
Men and Women: 15 mg
This RDA uses the following isomers of -tocopherol
RRR, RSR, RRS, RSS (note: all are 2R forms)
UL adults 1000 mg
Includes both R and S forms
For supplements only
Nutritional versus pharmacological levels
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Food Sources of Alphatocopherol (2R forms)
1.
Alpha-tocopherol has the highest
biological activity. Vegetables and
nuts are good sources.
2.
Plant oils usually are high in tocopherol and its content is usually
proportional to the PUFA in the oil.
3.
Corn and soybean oil are exceptions.
They are high in gamma-tocopherols.
Cottonseed oil is half/half for the
alpha and gamma forms.
4.
Coconut oil is mainly saturated f.a.
and is low in both PUFA and vitamin
E.
5.
Animal oils and fats, including marine
oils, are low in vitamin E.
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Digestion and Absorption
Fat intake needed for tocopherol absorption
Little vitamin E absorption without fat
Digested to free tocopherols
Bile and pancreatic secretions required
Absorption
Percent absorption varies depending upon intake
Dietary intake: ~ 15 45%
200 mg supplement: ~ 10%
Absorbed tocopherols are incorporated into
chylomicrons
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Transport
Chylomicrons
Some surface tocopherols will equilibrate with HDL
HDL will transport some tocopherols to other lipoproteins
Most tocopherols will stay in the chylomicron
Will remain in the chylomicron remnant and enter the liver
Liver metabolism
Liver sorts tocopherols
Alpha-tocopherol transfer protein (TTP)
Selects for RRR- tocopherol
Incorporated into VLDL
Some RRR- tocopherol transferred to HDL
VLDL
LDL
all tissues
Other tocopherol forms stay in the liver
Oxidized and excreted
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Storage and Excretion
Storage
Adipocytes predominate
This tocopherol is relatively unavailable
Liver
Muscle: Important, can be mobilized
Excretion
Tissue vitamin E transported back to liver
HDL involved in reverse transport of vitamin E
Oxidized in liver by cytochrome P450
Conjugated with glucuronate or sulfate
Excreted in bile and urine
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Vitamin E Metabolism
Antioxidant activity
Peroxyl radical scavenger in membranes
Reacts 1000 times faster with vitamin E than
with PUFA
ROO + Vit E-OH
ROOH + Vit E-O
In the absence of vitamin E, a chain reaction occurs
Vitamin E radical is reduced
Vit E-O + RH
Vit E-OH + A
The hydrogen donor is vitamin C or other H donors
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Vitamin E Oxidation
chr omanol r ing
C H3
H+
e-
HO
C H3
O
1.
H 3C
O
CH 3
The electron and proton are
removed from the OH. The
ionized oxygen becomes a
ketone. Double bonds move.
2.
Reduced with vitamin C,
glutathione, or other thiols and
double bonds move back.
3.
If not reduced, chromanol ring
is oxidized and broken. Vitamin
E has now been irreversibly
oxidized.
4.
R
Vitamin E will be conjugated in
the liver and excreted.
R
H 3C
CH 3
O
CH 3
CH 3
CH 3
Vi t C
glut athi one
other thi ols
H+
e-
O
R
H3C
O
CH3
CH3
eCH 3
O
R
H3C
O
CH3
CH3
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Interactions With Other Nutrients
Selenium
Both are involved in antioxidant actions
Complement each other
Vitamin C
Important in reducing the vitamin E radical
Vitamin K
High intakes of supplemental Vitamin E
Decreases vitamin K biomarkers
May interfere in vitamin K metabolism
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Vitamin E Deficiency 1
Premature infants
Low stores at birth
Malabsorb vitamin E for 8-12 weeks
Rapid growth
Vitamin E appears to be protective for
The retina of the eye
Red cells
Malabsorption conditions
Cystic fibrosis, Crohns disease, celiac disease
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Clinical Applications 1
Cardiovascular Disease: Self-selected
1991: Increased plasma Vit. E
Decreased angina pectoris
1993: ~ 100 IU protective against heart disease
Health Professionals Follow-up Study
Nurses Study
1995: Vit. E intake following coronary artery
bypass
Self selected for supplementation
Vit. E of 100 IU or more
Less progression of coronary lesions
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Clinical Applications 2
1995: Aspirin with 400 IU Vit. E
Fewer completed strokes in patients with TIAs
1996: Cambridge Heart Antioxidant Study
Acronym: CHAOS
400 and 800 IU vit. E
1 years, 2002 subjects
77% reduction in myocardial infarctions
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Clinical Applications 3
2000: Heart Outcomes Prevention
Evaluation
Acronym: HOPE
400 IU or placebo, 5 years
9500 subjects, high risk,
CHD or diabetes + 1 other risk factor
No significant difference
NEJM 2000; 342:154-60
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Clinical Applications 3
2005: Heart Outcomes Prevention
Evaluation
Acronym: HOPE
400 IU or placebo, 7 years
9500 subjects, high risk,
CHD or diabetes + 1 other risk factor
significant No difference
JAMA 2005; 293:1338-47
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Clinical Applications 4
Physicians Health Study II
Began 1997
Vitamin E and C component
Concl. 2007 Mean follow-up 8 years
Results: Nothing significant
Vit. C or Vit. E or Vit. C and E
Made no difference in men with or without
a history of CVD
JAMA 2008; 300: 2123-33
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Clinical Applications 5
Smokers
Vit. E decreased lipid peroxidation in red cells
Low-fat diets
Decreased Vit. E intake from dietary sources
Increased use of PUFA
Depends upon oil used
Adverse reactions
Finnish men, smokers
50 mg vit. E increased hemorrhagic stroke 50%
Vitamin E supplementation ???
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Vitamin K History
1929 - 1934: Henrik Dam (Copenhagen)
Chicks fed a fat free diet
Wing clip used to identify chicks in flock
Chicks had uncontrolled bleeding
Determined that other known vitamins were not involved and
that this was a new fat-soluble vitamin
Named vitamin K for Koagulation in Danish
1939 Edward Doisy (St Louis)
Chemistry of vitamin K
Isolated the pure preparation
Determined chemical nature
Synthetic preparation
1943 Dam and Doisy shared the Nobel Prize
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A
Vitamin K Deficiency
in Chicks
B
A. Spontaneous hemorrhages under the
skin of a chick fed a vitamin K-deficient
diet for the first 15 days.
B. Normal chick, the same age, but fed an
adequate diet
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Vitamin K History
1920s Vitamin K antagonist
Cattle eating moldy sweet clover
Developed bleeding disorder
Antagonist to vitamin K identified
Dihydroxycoumarol
Synthetic antagonists (anticoagulants)
Warfarin
Dicoumarol, coumadin
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All forms of tobacco appear
to be sources of vitamin K:
5 to > 1000 mg/100 g
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Dietary Recommendations & Intake
1989 RDA
> 15 years: 55 to 80 g
Based upon amount of Vit. K needed for
normal clotting
2001
Adequate Intake (AI)
Men 120 g
Women 90 g
Based on intakes of
apparently healthy
populations
No UL
Dietary intake Range: Means
Adults < 45 years 60-110 g: 80 g
> 55 years 80-210 g: 150 g
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O
CH 3
Vi tam in K-1 (phyl loquinone)
O
C
H2
H
C
C H3
C
H2
C
H2
(C
H2
C
C H3
C
H
H2
C )3 H
O
C H3
Vit ami n K- 2 (menaqui none)
CH3
(C
O
H2
C
H
C
H2
C)n H
n = 6,7, or 8
O
CH3
Vit ami n K- 3 (menadi one)
O
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OH
OH
H2
C
O
Dicoum arol
O
O
O
ON a
H
C
W arf ari n (sodi um sal t)
O
O
CH 2C OC H 3
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Absorption
Absorption primarily in jejunum
Bile and pancreatic juice required
Absorption require micelles, chylomicrons
Factors that may decrease absorption
Bile duct obstruction
Malabsorption syndromes
Celiac, inflammatory bowel disease,
pancreatic insufficiency
Systemic circulation
Stays in chylomicron and its remnant
Delivered to liver
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Fate in Liver
Liver (3 possibilities)
1. Stored (1-1.5 g/kg body wt.)
2. Oxidized to inactive products
3. Becomes part of lipoproteins
VLDL
LDL
HDL
Delivered to tissues
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Synthesis of Gamma-carboxy Glutamic Acid
sidec hain
C OO-
( KH2)
Vi tam in K
hydr oquinone
CO2
C H2
C H2
glut amic acid
i n pepti de
(KO)
Vi tam in K
2,3 epoxide
gl ut amy l car boxyl ase
O2
-
C OO-
OO C
HC
CH 2
carboxy gl utam ic aci d
in pept ide
Formation of Gla allows the peptide to bind Ca++
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car boxy glu-pept ide
pe ptide- glu
CO2
gl ut amy l car boxyl ase
II
OH
C H3
2
O
CH 3
O
R
KO - 2,3 epoxide O
OH
NAD or NADP
c ta
se
Thi ol
compounds
er
NAD H
or NADPH
war f arin
SH
ep
ox
id
S
du
re
S
II I
I
d ehyd rog enase
ed
uc
t as
e
hydroquinone
KH2
R
Thiol
com pounds
SH
SH
wa rf ari n
S
O
S
CH 3
SH
R
quinone
K
O
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Notes on Vitamin K cycle
Three reactions known as I, II, and III
Step I Makes vit. K hydroquinone
Two enzymes
Quinone reductase (uses thiol groups)
Considered to be the most important of the 2 enzymes
Action can be blocked by warfarin-type drugs
Quinone reductase (uses NADH or NADPH in liver)
Step II Makes Gla
Step III Regeneration of vitamin K
Warfarin-type drugs can block enzyme action
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App act
Compare and contrast E and K structures,
functions, and cycles
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Vitamin K is Required for
Normal Blood Clotting
4 factors
II prothrombin
VII Hageman factor
IX Christmas factor
X Stuart factor
3 proteins
C controls speed of clotting
S assists C
Z helps clot to bind to phospholipid surface
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Vitamin K-related Bone Proteins
1974 Osteocalcin identified
Secreted by osteoblasts during matrix formation
Binds calcium
Involved with bone remodeling
Warfarin can impair osteocalcins action
Matrix Gla protein (MGP)
Involved with bone, dentin, and cartilage
Protein S
Needed for bone calcification
Synthesis of proteins is also modulated by
Vitamin D
Retinoic acid
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Study on Vitamin K Intake and
Hip Fractures
1999 Nurses Study
Vitamin K intake divided into quintiles and
relative risk (RR) of hip fracture was determined
Vit. K intake
RR of hip fracture
1. < 109 g/day
2. 109-145 g/day
3. 146-183 g/day
4. 184-242 g/day
5. > 242 g/day
AJCN 1999; 69; 74-9
1.0
0.80
0.67
0.75
0.78
Lowest
fracture rate
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Vitamin K Antagonism
Human doses carefully regulated
Factors influencing the dose
Vitamin K intake (green vegetables)
Tobacco use
Can be overcome by high Vitamin K intakes
Uses Step I NADH or NADPH in liver with
reductases
Warfarin impact on Vitamin K in bone is not
reversed with high vitamin K intake
No NADH or NADPH reductases in bone for this
reaction
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Interactions with Other Nutrients
High vitamin A intake
Interferes with vitamin K intestinal absorption
Vitamin E
May interfere with Vitamin K metabolism
Vitamin D
Interactions with calcium
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Excretion
Vitamin K metabolized by cytochrome
P450 in liver
Oxidation of side chain
Conjugation with glucuronides or similar
substances making them more water soluble
Become part of bile, secreted into GI tract
Found in feces
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Clinical Applications 1
Newborn infants
Vitamin K given (0.5 to 1.0 mg) after birth
Given by injection
Increases prothrombin to good levels
Prevents bleeding problems
Surgery
If no vitamin K given after birth
Takes ~ 8 days for prothrombin to reach good levels
Breast milk is low in vitamin K
Commercial formula and cow milk are higher
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Clinical Applications 2
Coumadin therapy - Considerations
Vitamin K intake
Tobacco use
Reversal in an emergency
Bone density
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Summary
Vitamins E and K have similar digestion
and absorption
Vitamin E donates electrons
Vitamin K participates in carboxylation
reactions
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