The Vitamins 13710 ′- and 12′-apo-carotenals, which are oxidized to
yield retinoic acid, but are not precursors of retinol
or retinaldehyde.Plasma retinol binding protein
Retinol is released from the liver bound to an α-
globulin, retinol binding protein (RBP); this serves to
maintain the vitamin in aqueous solution, protects it
against oxidation and delivers the vitamin to target
tissues. RBP is secreted from the liver as a 1:1 complex
with the thyroxine-binding prealbumin, transthy-
retin. This is important to prevent urinary loss of
retinol bound to the relatively small RBP, which would
otherwise be fi ltered by the kidney, with a consider-
able loss of vitamin A from the body.
Cell surface receptors on target tissues take up
retinol from the RBP–transthyretin complex, trans-
ferring it on to an intracellular RBP. The receptors
also remove the carboxy-terminal arginine residue
from RBP, so inactivating it by reducing its affi nity for
both transthyretin and retinol. As a result, apo-RBP
is fi ltered at the glomerulus; most is reabsorbed in the
proximal renal tubules and hydrolyzed. The apopro-
tein is not recycled.
During the development of vitamin A defi ciency in
experimental animals, the plasma concentration of
RBP falls, whereas the liver content of apo-RBP rises.
The administration of retinol results in release of
holo-RBP from the liver. This provides the basis of
the relative dose–response (RDR) test for liver reserves
of vitamin A (see below).
Metabolic functions of vitamin A
and carotenes
The fi rst function of vitamin A to be defi ned was in
vision. More recently, retinoic acid has been shown to
have a major function in regulation of gene expres-
sion and tissue differentiation.
Vitamin A 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 hence
is sensitive to only one color of light. Color blindness
results from loss or mutation of one or other of the
cone opsins.
In the pigment epithelium of the retina, all-trans-
retinol is isomerized to 11-cis-retinol and then oxi-
dized to 11-cis-retinaldehyde. This reacts with a lysine
residue in opsin, forming the holoprotein rhodopsin.
As shown in Figure 8.3, the absorption of light by
rhodopsin causes isomerization of the retinaldehyde
bound to opsin from 11-cis to all-trans, and a confor-
mational change in opsin. This results in the release of
retinaldehyde from the protein and the initiation of a
nerve impulse. The overall process is known as bleach-
ing, since it results in the loss of the color of rho-
dopsin. The all-trans-retinaldehyde released from
rhodopsin is reduced to all-trans-retinol, and joins the
pool of retinol in the pigment epithelium for isomeri-
zation to 11-cis-retinol and regeneration of rhodop-
sin. The key to initiation of the visual cycle is the
availability of 11-cis-retinaldehyde, and hence vitamin
A. In defi ciency both the time taken to adapt to dark-
ness and the ability to see in poor light are impaired.
The excited form of rhodopsin (metarhodopsin II)
initiates a G-protein cascade leading to hyperpolar-
ization of the outer section membrane of the rod or
cone, caused by the closure of sodium channels
through the membrane, and the initiation of a nerve
impulse.Retinoic acid and the regulation of
gene expression
The main function of vitamin A is in the control of
cell differentiation and turnover. All-trans-retinoic
acid and 9-cis-retinoic acid are active in the regulation
of growth, development, and tissue differentiation;
they have different actions in different tissues. Like
the steroid hormones and vitamin D, retinoic acid
interacts with nuclear receptors that bind to response
elements (control regions) of DNA, and regulate the
transcription of specifi c genes.
There are two families of nuclear retinoid recep-
tors: 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, and some
of the other physiologically active retinoids as well.
RXR can form active dimers with RARs, RXRs
(homodimers), and the receptors for calcitriol
(vitamin D), thyroid hormone, long-chain polyun-
saturated fatty acid (PUFA) derivatives [the peroxi-
some proliferators-activated receptor (PPAR)], and
one for which the physiological ligand has not yet
been identifi ed (the COUP receptor).
The result of this is that a very large number of
genes are sensitive to control by retinoic acid in