Transcript 2. Only defined role: protects polyunsaturated fatty acids

Vitamin E and Selenium
Nov 6, 2013
Forms of vitamin E: alpha-tocopherol is the most active
1.
Tremendous hype as “wonder vitamin” – “prevents aging, heart disease,
cancer, improves sex life, promotes wound healing”.
Virtually none of this has been rigorously substantiated, but the vitamin
pushers work hard to keep the myth alive. (Dr. Handelman’s judgement!).
2.
Only defined role: protects polyunsaturated fatty acids (PUFA) from
peroxidation. Since the CNS, and the membranes of the mitochondria,
and are very rich in PUFA, vitamin E deficiency first attacks the central
nervous system and muscles.
All forms of vitamin E work pretty well, but only the a-tocopherol form is
tenaciously retained by the body (see below).
3.
Deficiency in humans takes many years to develop, since we store
several grams in our fat tissues. First tissue to be damaged is the retina,
since the retina is very rich in fatty acids with 6 double bonds.
4.
Long-term deficiency leads to spinal cord degeneration and muscle
atrophy.
5.
If your diet is high in PUFA, such as from fish, you more vitamin E
in your diet. However, since vitamin E is plentiful in whole grains,
vegetable oils, and green vegetables, even people who eat a lot of
seafood get enough for health, and they don’t need supplemental
vitamin E.
6.
Since vitamin E is NOT water-soluble, it is transported in the bloodstream in
the lipoprotein particles (LDL and HDL). The diagram in the handout shows why
only form, RRR-alpha-tocopherol, is conserved in the tissues.
PEOPLE WHO LACK THIS BINDING PROTEIN require high daily doses of
a-tocopherol to avoid being deficient.
7.
Since 1990, there have been 4 large trials of vitamin E supplements to prevent
heart disease – none has been effective, but other interventions (aspirin, ACE
inhibitors, drugs to lower cholesterol) have been quite effective!
INITIAL FORMATION OF A PEROXYL RADICAL
FROM UNSATURATED FATTY ACID
IF THESE EVENTS OCCUR IN THE MEMBRANE,
THERE CAN BE SUBSTANTIAL DISTURBANCE TO
THE STRUCTURE OF THE BILAYER, AS THE
DAMAGED FATTY ACID “STICKS OUT”.
THIS TRIGLYCERIDE HAS
TWO SATURATED FATTY ACIDS, AND
ONE POLYUNSATURATED FATTY ACID
PALMITIC ACID: SATURATED FAT
OLEIC ACID (1 DOUBLE BOND):
MONOUNSATURATED FAT
These fatty acids do not peroxidize.
Which foods contain a lot of these fatty acids?
THESE ARE TWO IMPORTANT POLYUNSATURATED
FATTY ACIDS. THEY HAVE A VERY POWERFUL
IMPACT ON NUTRITION.
BOTH OF THESE FATTY ACIDS PEROXIDIZE
THESE ARE TWO IMPORTANT POLYUNSATURATED
FATTY ACIDS. THEY HAVE A VERY POWERFUL
IMPACT ON NUTRITION.
THESE FATTY ACIDS ARE OBTAINED FROM SEAFOOD,
IN ADDITION TO BEING MADE IN YOUR TISSUES. THEY ARE
MAJOR COMPONENTS OF THE CNS AND RETINA.
THEY PEROXIDIZE VERY FAST,
WHICH IS WHY FISH DOES NOT KEEP WELL.
THE VERY HIGH ABUNDANCE OF EPA
AND DHA IN THE BRAIN AND RETINA
EXPLAINS:
WHY THE MAJOR LESIONS
OF VITAMIN E DEFICIENCY IN HUMANS
OCCUR IN THE CNS.
INITIAL FORMATION OF A PEROXYL RADICAL
FROM UNSATURATED FATTY ACID
THIS RADICAL
ATTACKS
ANOTHER FATTY
ACID WITH MANY
DOUBLE BONDS
Once an initial radical attack is made on a fatty acid –
The first fatty acid radical will attack ANOTHER
unsaturated fatty acid.
Then another, and another.
The first radical attack can lead to the destruction
of hundreds of polyunsaturated fatty acids.
VITAMIN E TO THE RESCUE!
CH3•
Alpha-Tocopherol
Methyl
radical
(dangerous)
CH4
+
•
Methane
Tocopheroxy radical (harmless)
In this scenario, the methyl radical reacts directly with vitamin E,
to form methane, and the harmless tocopheroxy radical.
MORE TYPICALLY, VITAMIN E
REACTS WITH LIPID-OO• RADICALS
TOCOPHEROL
DONATES HERE
TO CREATE THE
LIPID PEROXIDE
PRODUCT
.
VITAMIN E CONVERTS THE VERY DANGEROUS
ROO• INTO THE LESS DANGEROUS ROOH
(lipid hydroperoxide).
IT IS NOW UP TO Glutathione peroxidase
TO REMOVE THE ROOH.
VITAMIN E AND GLUTATHIONE PEROXIDASE
WORK TOGETHER IN THE CELL.
Glutathione peroxidase
(abbreviated, “GSH-Px”
is a Selenium-Dependent ENZYME
that converts peroxides to alcohols.
The electrons for this reduction
come from glutathione (GSH).
+ GSH-Px
(active enzyme)
H
Product is ~harmless
alcohol of fatty acid
+ GSH-Px
(inactive enzyme)
GSH-Px
(inactive)
+ 2 GSH
GSH-Px
(active)
+ GSSG
The enzyme is then reactivated by glutathione.
Glutathione reductase enzyme
GSSG + NADPH
2 GSH + NADP+
Finally, all the GSSG is converted back to GSH
H
GSH
GSH-disulfide
(or GSSG)
1)
Fatty-acid-OOH + GSH-Px (active)
2) GSH-Px (inactive) + 2 GSH
3) GSSG + NADPH
Fatty-acid-OH +GSH-Px (inactive)
GSH-Px (active) + GSSH
2 GSH + NADP+
THE GLUTATHIONE PEROXIDASE PATHWAY.
The first step requires selenium.
CONSERVATION OF RRR-alpha-TOCOPHEROL
BY THE HEPATIC BINDING PROTEIN
BILE: Largely
gamma-T
Others forms of
vitamin E
LIVER
RRR-atocopherol
Chylomicron remnants, containing
all different forms of vitamin E
Bloodstream
Lymph chylomicrons
Intestinal lumen
DIET: Many forms of vitamin E
RRR-alpha-tocopherol
other isomers of alpha-T
gamma-tocopherol
delta-tocopherol
tocotrienols
Binding protein
grabs alpha-T
VLDL
Bloodstream
(mostly, alpha-T)
LDL
A-TOCOPHEROL IS RAPIDLY EXCRETED
IF THE BINDING PROTEIN IS DEFECTIVE
BILE: alpha-T
and gamma-T
Others forms of
vitamin E
LIVER
RRR-atocopherol
Chylomicron remnants, containing
all different forms of vitamin E
Bloodstream
Lymph chylomicrons
Intestinal lumen
DIET: Many forms of vitamin E
RRR-alpha-tocopherol
other isomers of alpha-T
gamma-tocopherol
delta-tocopherol
tocotrienols
Binding protein
grabs alpha-T
VLDL
Bloodstream
(mostly, alpha-T)
LDL