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Vitamin C
Vitamin C
• Vitamin C also known as ascorbic acid or
ascorbate.
• The human being is one of the few mammals
unable to synthesize vitamin C.
• Other animals unable to synthesize vitamin C
include primates, fruit bats, guinea pigs, and
some birds.
• The inability to synthesize vitamin C results from
the lack of gulonolactone oxidase, the last
enzyme in the vitamin C synthetic pathway.
History of Vitamin C
• Vitamin C was isolated in 1928, and its
structure was determined in 1933.
• The problems referred to as scurvy and
associated with the lack of vitamin C had been
quite prevalent for centuries. Some of the
most notable stories are those of the British
sailors who often died from scurvy on sea.
Vitamin C structure
Vitamin C
• Vitamin C have a number of vitamiers that
have vitamin C activity in animals:
• Ascorbic acid in biological system (low pH)
• Oxidized form deyhroascorbic acid.
• Ascorbate in neutral salutation (pH>5)
• Ascorbate and ascorbic acid are both naturally
present in the body, since the forms
interconvert according to pH.
Sources
• Fruits, vegetables and organ meats (liver, kidney).
• The best food sources of vitamin C include
asparagus, papaya, oranges, cantaloupe,
cauliflower, broccoli, green peppers, grapefruit,
grapefruit, lemons, and strawberries.
• Citrus products are most commonly cited as
significant sources of the vitamin.
• Supplements supply vitamin C typically as free
ascorbic acid, calcium ascorbate, sodium
ascorbate, and ascorbyl palmitate.
Sensitivity of vitamin C
• Very significant losses occur as vegetables
wilt, or when they are cut, as a result of the
release of ascorbate oxidase from the plant
tissue.
• Significant losses of the vitamin also occur in
cooking, both through leaching into the
cooking water and also atmospheric oxidation,
which continues when foods are left to stand
before serving.
DIGESTION, ABSORPTION &
TRANSPORT
• Vitamin C does not require digestion prior to being
absorbed into intestinal cells.
• There is active transport of the vitamin at the
intestinal mucosal brush border membrane. Both
ascorbate and dehydroascorbate are absorbed across
the buccal mucosa by carrier-mediated passive
processes.
• Intestinal absorption of dehydroascorbate is carrier
mediated, followed by reduction to ascorbate before
transport across the membrane.
DIGESTION, ABSORPTION &
TRANSPORT
• Prior to absorption, ascorbic may be oxidized
to dehydroascorbate, which may be absorbed
by facilitated diffusion.
• Although dehydroascorbic acid is absorbed in
higher rate than ascorbate, the amount of
dehydroascorbic acid found in plasma and
tissues under normal conditions is low, as cells
rapidly reduce dehyroascorbic acid to
ascorbate.
DIGESTION, ABSORPTION &
TRANSPORT
• Simple diffusion (may occur in stomach and
small intestine) provides for vitamin C
absorption with ingestion of higher amounts of
the vitamin.
• Anion channels in some cells may mediate
vitamin C diffusion faster than the transporters.
• From intestinal cells, ascorbate may diffuses
through anion channels into extracellular fluid
and enters plasma by way of capillaries.
DIGESTION, ABSORPTION &
TRANSPORT
• Within intestinal cells:
• Dehydroascorbic acid is rapidly reduced back to
ascorbic acid by enzyme dehydroascorbate
reductase.
• Glutathione (GSH), which is required for the
reduction of dehydroascorbate, is oxidized in
process. Glutathione spares vitamin C and, in
general, improves the antioxidant protection
capacity of blood.
• Degree of vitamin C absorption decrease with
increased vitamin intake.
DIGESTION, ABSORPTION &
TRANSPORT
• Some 80–95% of dietary ascorbate is
absorbed at usual intakes (up to about 100
mg/day).
• The fractional absorption of larger amounts of
the vitamin is lower, and unabsorbed
ascorbate from very high doses is a substrate
for intestinal bacterial metabolism, causing
gastrointestinal discomfort and diarrhea.
The redox cycling of ascorbate in chloroplast
DIGESTION, ABSORPTION &
TRANSPORT
• Absorption of ascorbate may be diminished in the
presence of high intracellular glucose, which
appears to interfere with ascorbate transporter.
• Unabsorbed vitamin C may be metabolized by
intestinal flora.
• Ingesting large amounts of iron with vitamin C
may result in oxidative destruction of vitamin C in
digestive tract, yielding other products without
vitamin C activity.
DIGESTION, ABSORPTION &
TRANSPORT
In plasma:
• Ascorbic acid is transported in the plasma
primarily in free form as an ascorbate anion.
• Normal plasma level of vitamin C 0.4 – 1.7 mg/dL.
In cells:
• Uptake of ascorbate into body cells requires
sodium and a carrier and into some cells such as
leukocytes, uptake is also energy dependent.
• Tissue concentrations of vitamin C usually exceed
plasma concentrations.
DIGESTION, ABSORPTION &
TRANSPORT
• Ascorbate and dehydroascorbate concentrations are
much greater in some tissues than others. The highest
in adrenal and pituitary glands (~30-50mg/100 g of wet
tissue).
• Intermediate in liver, spleen, heart, kidneys, lungs
pancreas and leukocytes.
• Smaller amounts in muscles and red blood cells.
• Maximal vitamin C pool is estimated at about 1.500mg.
• Intakes of about 100-200mg vitamin C/d have been
shown to produce plasma concentrations of about
1.0mg/dL and to maximize body pool.
Summary of absorption
• Absorbed in the intestine by an energy-requiring,
sodium- dependent, carrier- mediated transport
system.
• After absorption, ascorbic acid is then
transported as a free acid in plasma into the cells,
including leukocytes and red blood cells.
• In the tissues, Vitamin C serves as an electron
donor for a number of enzymes.
Function & mechanism of action
• Vitamin C has very complex functional roles in the body as a
cofactor in around eight reactions:
1. Collagen synthesis
2. Carnitine synthesis
3. Tyrosine synthesis and catabolism
4. Neurotransmitter synthesis.
5. Drug and steroid metabolism.
6. Maintain the iron and copper atoms in the metalloenzymes
in the reduced state.
7. In addition vitamin C acting role as reducing agent in
enzymatic reactions.
8. Ascorbate may also act as an antioxidant against oxidative
stress.
Collagen Synthesis
• Most abundant protein found in the body.
• Vitamin C is necessary for collagen synthesis.
• Collagen is a structural protein found in skin, bones, tendons, and
cartilage.
• All collagen (n~19) have a triple helical structure.
• For the collagen molecule to aggregate into its triple-helix
configuration selected proline residues must be hydroxylated forming
hydroxyproline.
• Requires di-oxygenase enzymes, reduced iron (Fe+2), ascorbate.
• Vitamin C role:
• During hydroxylation, iron cofactor in the enzymes is oxidized,
(ferrous(2+) state ---- ferric (3+) state).
• Ascorbate is needed to function as a reductant thereby reducing iron
back to its ferrous (2+) in prolyl and lysyl hydroxylases.
Collagen Synthesis
• Vitamin C may also influence mRNA levels
needed for collagen synthesis.
• Although these reactions may seen simple,
normal development and maintenance of
skin, tendons, cartilage, bone and dentine
depend on an adequate supply of vitamin C.
• Also, important in wound healing and
bleeding prevention from capillaries.
Collagen Synthesis
Carnitine synthesis
Carnitine is a methylated from nitrogen containing
compound made from lysine.
• Sufficient carnitine is critical in fat metabolism,
because it is essential to transport long- chain
fatty acids from cell cytoplasm into mitochondrial
matrix where β-oxidation occurs.
Vitamin C role:
• Required for 2 hydroxylation reaction in synthesis
carnitine, which functions as preferred reducing
agent, specifically reducing Fe from ferric (Fe3+ )
back to ferrous state (Fe2+ ).
Tyrosine synthesis & catabolism
• Tyrosine synthesis
• Hydroxylation of phenylalanine
• Requires phenylalanine mono-oxygenase (hydroxylase),
Fe+2. O2. tetrahydrobiopterin, NADPH, vitamin C
• Vitamin C regenerating tetrahydro-biopterin from
dihydrobiopterin.
• Occurs in liver and kidney.
• Tyrosine catabolism require ascorbate as reductant for
hydroxylases
• Cu-dependent enzyme p-hydroxyphyenylpyruvate
(dioxygenase)
• Fe-dependent enzyme homogentisate dioxygenase.
Neurotransmitter synthesis
• Vitamin C maintains mineral cofactors for some
of the enzymes involved in synthesis of
neurotransmitters in its reduced state.
Norepinephrine
• It is generated from hydroxylation of dopamine
side chain.
• This reaction catalyzed by dopamine
monoxygenase (contain 8 Cu atoms)-vitamin Cdependent reaction.
• Found in nervous tissue and adrenal medull.
Dopamine Hydroxylase
Neurotransmitter synthesis
• Serotonin
• Hydroxylation of tryptophan (in brain)
• Requires tryptophan mono-oxygenase (hydroxylase),
O2 tetrahydrobiopterin, vitamin C. first step in
serotonin synthesis.
• Other Neurotransmitters and Hormones
•
keeping Cu in reduced for peptidylgycine α-amidating
mono-oxygenase.
• Many of amidated peptides are active as hormones,
such as calcitonin, CCK and gastrin.
• The enzyme found in pituitary , adrenal, thyroid glands
and brain.
Summary
• Vitamin C acts as an electron donor for 8 different
enzymes:
• Three enzymes participate in collagen hydroxylation.
• Two enzymes are necessary for synthesis of carnitine.
• Three remaining enzymes have the following functions
in common, but have other functions as well:
• Dopamine β-hydroxylase participates in biosynthesis of
norepinephrine from dopamine.
• Enzyme adds amide groups to peptide hormones.
• One modulates tyrosine metabolism.
Microsomal metabolism
• A group of enzymes makes up a microsomal
metabolizing system, mostly function in liver, to
inactivate both endo-and exogenous substances.
• Endogenous: Include various hormones and
steroids (cholesterol)
• Exogenous: xenobiotics (foreign chemicals) drugs,
carcinogens, pesticides, pollutants, food additives
• The reactions to metabolize these substances
usually involve hydroxylation's followed by other
reactions to produce polar metabolites for
excretion.
Antioxidants activity
• The reduction potential of ascorbate is such that it
readily donates electrons/hydrogen ions to regenerate
other antioxidants, such as vitamin E, glutathione, and
uric acid, and to reduce numerous reactive oxygen
(ROS) and nitrogen species (RNS).
• Ascorbic acid interact with oxidants in the aqueous
phase (blood or intracellular) before they initiate
damage in nucleus, cell lipids.
• Ascorbate = thiols > bilirubin > uric acid > vitamin E
Pro-oxidant activity
• Vitamin C can reduce transition metals, while
itself becoming oxidized to
semidehydroascorbate:
Ascorbate (AH2) +Fe3+ or Cu2Semidehydroascorbate radical (AH−) + Fe2+ or Cu1+
• These reduced metal ions can cause cell damage by
generating ROS and free radicals.
Fe2+ or Cu1+ + H2O2
Fe3+ or Cu2- + H2O2 + OH
Fe2+ or Cu1+ + O2
Fe3+ or Cu2- + O2-
Other functions
• Vitamin C and colds:
Vitamin C is thought to moderate colds by
enhancing many immune cell (such as some
leukocyte) functions while also destroying
histamine, which causes many of a cold’s
symptoms.
Other functions
• Vitamin C and cancer:
• It is controversial issue due to:
• Epidemiological studies suggest inverse relationship
between vitamin C and cancers of oral cavity,
esophagus and stomach.
• Clinical studies:
• Some shown that survival time in cancer time patients
may be prolonged, possible protective mechanisms
• Ability to act as a reducing agent
• Detoxify carcinogens.
Other functions
• CVD:
• Many (but not all) epidemiological and prospective studies
report that increased fruit and vegetable intake, vitamin C
intake, and plasma vitamin C concentration are associated
with decreased risk of heart disease.
• Low vitamin C status also is related to increased blood
total cholesterol concentrations, whereas high plasma
vitamin C concentrations have been associated with lower
blood pressure and with higher plasma high-density
lipoprotein cholesterol concentrations, both of which are
protective against heart disease.
• studies with supplements of vitamin C and other
antioxidants have not reported beneficial effects.
Other functions
• Cataracts:
negative relation with vitamin c
• Bone density:
Positive relation with vitamin C
• Wound healing and connective tissue
metabolism.
INTERACTIONS WITH OTHER NUTRIENTS
• Vitamin C and iron
• Increase intestinal absorption of non-heme iron
• Reduce Fe3+ to Fe2- forms a soluble complex with
iron in alkaline pH of SI.
• Effect on iron distribution in the body.
• Vitamin C aids incorporation of iron into ferritin
• Excessive iron in presence of vitamin C can
accelerate oxidative catabolism of vitamin C.
Interactions with other nutrients
• Vitamin C and copper
• May increase absorption and excretion of heavy
metals
• Vitamin C intakes above 600 mg/d may interfere
with copper metabolism.
• Vitamin C helps keep folate in its reduced and
active form.
Excretion
• Excretion reduced when intake is low
• Urinary excretion
• Body pool <1.500mg leads to only metabolites
in urine
• Body pool > 1500mg leads to proportionately
more ascorbate in urine
• Vitamin C may be excreted intact or oxidized
by L-ascorbate oxidase to oxalic acid, primarily
in liver and some in kidney.
Vitamin C RDA
•
•
•
•
•
•
Adult male: 90mg
Adult female: 75 mg
Pregnancy: 100my
Lactating: 120mg
Smokers: extra 35 mg
UL: adult 2000 mg.
Deficiency
• Scurvy
• Scurvy leads to formation of brown spots on skin,
bleeding gums, small red skin discolorations
caused by ruptured small blood vessels
(petechiae), sublingual hemorrhages, easy
bruising (ecchymoses and purpurae), impaired
wound and fracture healing, joint pain
(arthralgia), loose and decaying teeth, and
hyperkeratosis of hair follicles, especially on the
arms, legs, and buttocks.
Scurvy
Toxicity
• Toxicity is rare.
• Tolerable upper intake level of 2g vitamin C/d
• The most common side effect with ingestion of
large amounts (2 g) of the vitamin is
gastrointestinal problems characterized by
abdominal pain and osmotic diarrhea.
• Other side effects include increased risk of kidney
stones and iron toxicity for those with renal
disease and disorders of iron metabolism.