Vitamin A & D

Chemistry, biochemical role, RDA &

deficiency diseases
 Introduction
Vitamins
• group of organic nutrients required in small quantities for a variety of biochemical functions
• cannot be synthesized by the body
• supplied in the diet.
Lipid-soluble vitamins are
• a polar hydrophobic compounds that can only be absorbed efficiently when there is normal fat absorption.
• transported in the blood, like any other a polar lipid, in lipoproteins or attached to specific binding proteins.
Diverse functions:
– eg, vitamin A, vision;
– Vitamin D, calcium and phosphate metabolism
– vitamin E, antioxidant;
– vitamin K, blood clotting.
• dietary inadequacy, conditions affecting the digestion and absorption of the lipid-soluble vitamins—such as
steatorrhea and disorders of the biliary system—can all lead to deficiency syndromes
– night blindness and xerophthalmia (vitamin A);
– rickets in young children and
– osteomalacia in adults (vitamin D);
– neurologic disorders and
– anemia of the newborn (vitamin E); and
– hemorrhage of the newborn (vitamin K).
 Introduction
• Toxicity can result from excessive intake of vitamins A and D.
• Vitamin A and β-carotene (provitamin A), as well as vitamin E, are antioxidants and
have possible roles in atherosclerosis and cancer prevention.
• The water-soluble vitamins comprise the B complex and vitamin C and function as
enzyme cofactors.
• Folic acid acts as a carrier of one-carbon units.
• Deficiency of a single vitamin of the B complex is rare, since poor diets are most
often associated with multiple deficiency states.
• specific syndromes are characteristic of deficiencies of individual vitamins, eg,
beriberi (thiamin); cheilosis, glossitis, seborrhea (riboflavin); pellagra (niacin);
peripheral neuritis (pyridoxine); megaloblastic anemia, methylmalonic aciduria,
and pernicious anemia (vitamin B12); and megaloblastic anemia (folic acid).
• Vitamin C deficiency leads to scurvy.
• Inorganic mineral elements that have a function in the body must be provided in
the diet.
• When the intake is insufficient, deficiency symptoms may arise, eg, anemia (iron),
cretinism and goiter (iodine).
• If present in excess as with selenium, toxicity symptoms may occur.
RETINOIDS & CAROTENOIDS HAVE VITAMIN A ACTIVITY

• Retinoids comprise retinol, retinaldehyde, and retinoic acid (preformed vitamin A, found only in
foods of animal origin);
• carotenoids, found in plants, comprise carotenes and related compounds, known as provitamin A,
as they can be cleaved to yield retinaldehyde and thence retinol and retinoic acid.
• a, b ,and g-carotenes and cryptoxanthin are quantitatively the most important provitamin A
carotenoids.
• one molecule of b- carotene should yield two of retinol, 6 mg of b-carotene is equivalent to 1 mg
of preformed retinol.
• total amount of vitamin A in foods is therefore expressed as micrograms of retinol equivalents.
• Beta-carotene and other provitamin A carotenoids are cleaved in the intestinal mucosa by
carotene dioxygenase, yielding retinaldehyde, which is reduced to retinol, esterified, and secreted
in chylomicrons together with esters formed from dietary retinol.
• intestinal activity of carotene dioxygenase is low, so that a relatively large proportion of ingested
β-carotene may appear in the circulation unchanged.
• While the principal site of carotene dioxygenase attack is the central bond of β-carotene,
asymmetric cleavage may also occur, leading to the formation of 8’-, 10’-, and 12’-apo-carotenals,
which are oxidized to retinoic acid but cannot be used as sources of retinol or retinaldehyde.
 b-carotene and the major vitamin A vitamers.
* shows the site of cleavage of b -carotene into two molecules of retinaldehyde
by carotene dioxygenase.
 Vitamin A Has a Function in Vision

• In the retina, retinaldehyde functions as the prosthetic group of the light-sensitive opsin proteins,
forming rhodopsin (in rods) and iodopsin (in cones).
• Any one cone cell contains only one type of opsin and is sensitive to only one color.
• In the pigment epithelium of the retina, all-trans-retinol is isomerized to 11-cis-retinol and oxidized to
11-cis-retinaldehyde. This reacts with a lysine residue in opsin, forming the holoprotein rhodopsin.
• The absorption of light by rhodopsin causes isomerization of the retinaldehyde from 11-cis to all-
trans, and a conformational change in opsin.
• This results in the release of retinaldehyde from the protein and the initiation of a nerve impulse.
• The formation of the initial excited form of rhodopsin, bathorhodopsin, occurs within picoseconds of
illumination.
• There is then a series of conformational changes leading to the formation of metarhodopsin II, which
initiates a guanine nucleotide amplification cascade and then a nerve impulse.
• The final step is hydrolysis to release all-trans-retinaldehyde and opsin.
• The key to initiation of the visual cycle is the availability of 11-cis-retinaldehyde, and hence vitamin A.
• In deficiency, both the time taken to adapt to darkness and the ability to see in poor light are
impaired.
The role of retinaldehyde in vision
 Retinoic Acid has a Role in the Regulation of Gene Expression &
Tissue Differentiation

• A most important function of vitamin A is in the control of cell

differentiation and turnover.
• All-trans retinoic acid and 9-cis-retinoic acid regulate growth,
development, and tissue differentiation;
• they have different actions in different tissues.
• Like the steroid hormones and vitamin D, retinoic acid binds to
nuclear receptors that bind to response elements of DNA and
regulate the transcription of specific genes.
• There are two families of nuclear retinoid receptors:
• the retinoic acid receptors (RARs) bind all-trans-retinoic acid or 9-
cis-retinoic acid, and
• the retinoid X receptors (RXRs) bind 9-cis-retinoic acid.
 Vitamin A Deficiency

• Vitamin A deficiency is the most important preventable cause of

blindness.
• The earliest sign of deficiency is a loss of sensitivity to green light,
followed by impairment of adaptation to dim light, followed by night
blindness.
• More prolonged deficiency leads to xerophthalmia: keratinization of
the cornea and skin and blindness.
• important role in differentiation of immune system cells, and mild
deficiency leads to increased susceptibility to infectious diseases.
• synthesis of retinol-binding protein in response to infection is reduced
(it is a negative acute phase protein), decreasing the circulating
vitamin, and therefore there is further impairment of immune
responses.
 Vitamin A Toxicity

• only a limited capacity to metabolize vitamin A, and excessive

intakes lead to accumulation beyond the capacity of binding
proteins, so that unbound vitamin A causes tissue damage.
• Symptoms of toxicity affect the central nervous system
(headache, nausea, ataxia, and anorexia, all associated with
increased cerebrospinal fluid pressure),
• the liver (hepatomegaly with histologic changes and
hyperlipidemia),
• calcium homeostasis (thickening of the long bones,
hypercalcemia and calcification of soft tissues), and the skin
(excessive dryness, desquamation, and alopecia).
 Requirements

Recommended daily requirement of Vitamin A

for
– adults is 750mg.
– infants and young children is 300 mg.
– women during pregnancy and lactation require
1200 mg per day
 VITAMIN D

• Vitamin D is not strictly a vitamin since it can be synthesized

in the skin, and under most conditions that is its major
source.
• Only when sunlight is inadequate is a dietary source required.
• The main function of vitamin D is in the regulation of calcium
absorption and homeostasis;
• most of its actions are mediated by way of nuclear receptors
that regulate gene expression.
• Deficiency—leading to rickets in children and osteomalacia
in adults—continues to be a problem in northern latitudes,
where sunlight exposure is poor.
 Vitamin D Is Synthesized in the Skin

• 7-Dehydrocholesterol (an intermediate in the synthesis of

cholesterol that accumulates in the skin), undergoes a
nonenzymic reaction on exposure to ultraviolet light, yielding
previtamin D.
• This undergoes a further reaction over a period of hours to
form the vitamin itself, cholecalciferol, which is absorbed into
the bloodstream.
• In temperate climates, the plasma concentration of vitamin D is
highest at the end of summer and lowest at the end of winter.
• Beyond about 40 degrees north or south in winter, there is very
little ultraviolet radiation of appropriate wavelength.
Synthesis of vitamin D in the skin .
 Vitamin D Is Metabolized to the Active Metabolite, Calcitriol, in
Liver & Kidney

• In the liver, cholecalciferol, which has been synthesized in the

skin or derived from food, is hydroxylated to form the 25-
hydroxy derivative calcidiol .
• This is released into the circulation bound to a vitamin D-
binding globulin which is the main storage form of the vitamin.
• In the kidney, calcidiol undergoes either 1-hydroxylation to
yield the active metabolite 1,25-dihydroxy vitamin D (calcitriol)
or 24-hydroxylation to yield an inactive metabolite, 24,25-
dihydroxyvitamin D (24- hydroxycalcidiol).
• Ergocalciferol from fortified foods undergoes similar
hydroxylations to yield ercalcitriol.
Metabolism of vitamin D
 Vitamin D Metabolism both Regulates & is Regulated by Calcium
Homeostasis

• main function of vitamin D is in the control of calcium homeostasis, and in turn

vitamin D metabolism is regulated by factors that respond to plasma
concentrations of calcium and phosphate.
• Calcitriol acts to reduce its own synthesis by inducing the 24-hydroxylase and
repressing the 1-hydroxylase in the kidney.
• Its principal function is to maintain the plasma calcium concentration.
• Calcitriol achieves this in three ways:
– it increases intestinal absorption of calcium, reduces excretion of calcium (by stimulating
resorption in the distal renal tubules), and
– mobilizes bone mineral.
– In addition, calcitriol is involved in insulin secretion, synthesis and secretion of
parathyroid and thyroid hormones, inhibition of production of interleukin by activated T
lymphocytes and of immunoglobulin by activated B lymphocytes, differentiation of
monocyte precursor cells, and modulation of cell proliferation.
– In its actions, it behaves like a steroid hormone, binding to a nuclear receptor protein.
Vitamin D Deficiency Affects Children & Adults

• In the vitamin D deficiency disease rickets, the bones of

children are undermineralized as a result of poor
absorption of calcium.
• Similar problems occur in adolescents who are deficient
during their growth spurt.
• Osteomalacia in adults results from demineralization of
bone in women who have little exposure to sunlight, often
after several pregnancies.
• Although vitamin D is essential for prevention and
treatment of osteomalacia in the elderly, there is little
evidence that it is beneficial in treating osteoporosis.
 Vitamin D is Toxic in Excess

• Some infants are sensitive to intakes of vitamin D as low

as 50 μg/d, resulting in an elevated plasma concentration
of calcium.
• This can lead to contraction of blood vessels, high blood
pressure, and calcinosis—the calcification of soft tissues.
• Although excess dietary vitamin D is toxic, excessive
exposure to sunlight does not lead to vitamin D
poisoning because there is a limited capacity to form the
precursor 7-dehydrocholesterol and to take up
cholecalciferol from the skin.