Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

III. Fat-Soluble Vitamins
701
Major metabolic conversions of Vitamin A
3,4-didehydro-Retinol
Retinyl
Esters
VITAMIN A
(RETINOL)
14-hydroxy-retro Retinol
Retinyl palmitate
Retinyl Stearate
Retinyl Oleate
Retinyl Linoleate
Retinyl Palmitoleate
Retinaldehyde
(Retinal)
Retinyl β-glucuronide
Retinoic acid
(“Active” Form)
9,13 di-cis RA
9-cis RA
All-trans RA
13-cis RA
11,13 di-cis RA
18-hydroxyRA
4-hydroxyRA
Retinyl β-glucuronide
18-oxoRA
4-oxoRA
FIGURE 23-6 Steps in the metabolic conversion of vitamin A. The catabolism of excess retinol/retinal may be initiated by one of several alcohol
dehydrogenase isozymes with subsequent oxidation via peroxisomal enzymes. Microsomal enzymes (cytochrome P450 hydroxylases) are also involved.
Shown are some of some of the events and products. Some of these products may become sufficiently oxidized so that they are excreted by the kidney.
Others, such as the glucuronide, are deposed by transport and eventual delivery into bile.
from photons of light to electrochemical signals. The series
of events leading up the propagation of this signal are as follows:
vitamin A as 11- cis retinal, forms a protonated Schiff
base by binding to a lysine residue in the protein opsin to
yield the visual pigment, rhodopsin ( Lamb and Pugh, 2004 ).
When a photon of light strikes rhodopsin, cis-trans isomerization
occurs and the process results in a highly strained
form of rhodopsin, bathorhodopsin, which is converted to
metarhodopsin with subsequent deprotonation ( Jang et al.,
2000 ). The deprotonated metarhodopsin interacts with transducin,
one of the proteins in the transmembrane G-protein
family. This interaction causes a subunit of transducin to
bind GTP and stimulate cGMP phosphodiesterase activity.
This results in a decrease in cGMP, which constitutes a significant
amplification of the initiating event, the conversion
of light-derived energy through 11- cis to transisomerization
of retinal and specific changes in protein conformation
( Fig. 23-7 ). Next, the local change in cGMP concentration
results in changes in cation flux (Na and Ca ions) across
rod cell membranes ( Lamb and Pugh, 2004 ; McCabe
et al., 2004 ). This initiates an electrochemical event, the
firing of cells of the optic nerve. Further, metarhodopsin
is phosphorylated during these final steps and interacts
with a protein designated as arrestin. The metarhodopsinarrestin
complex inhibits the transducin response and causes
the release of all- trans retinal and the return to rhodopsin
(opsin), thus completing the cycle.
In quantitative terms, only a small fraction of the total
vitamin A requirement is involved in the visual process
because of extensive recycling of retinal. With vitamin A
deficiency, there is an inability to appropriately saturate
opsin with 11- cis retinal to form rhodopsin and its subsequent
complexes. This decreases the sensitivity of the
visual apparatus, so that light of low intensity is not perceived
leading to nyctalopia or night blindness. An important
note, which underscores the importance of having
some knowledge of vitamin A chemistry and physiology,
is that night blindness is not uncommon in cattle or sheep
that have been grazing on dry weathered pasture for long
periods such as during prolonged drought ( Barnett et al.,
1970 ; Booth et al., 1987 ). Although most cattle in feedlots
are supplemented with vitamin A, if vitamin A is accidentally
left out of the ration and stored hay is fed that has lost
its carotene content or grain (other than yellow corn), night
blindness can occur.
5 . Growth and Cell Differentiation
As work on vitamin A progressed, it became appreciated
that although retinol and retinal were important to vision,
the retinoic acid would not correct night blindness but was
essential to growth and normal development ( Debier and
Larondelle, 2005 ). Within cells all- trans retinol associates
with cytosolic retinol-specific binding proteins, and the
resulting complex become vehicles for subsequent processing.
For example, all- trans retinol may be oxidized and
isomerized to all- trans , 9- cis , or 13- cis retinoic acid, which
subsequently binds to retinoic acid-specific binding proteins
that act as transcription factors in protein regulation
and cellar differentiation ( Fig. 23-8 ). The details of such
interactions are beyond the scope of this chapter. However,
it is important to appreciate that in response to very low