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

III. Fat-Soluble Vitamins
705
Diet
7-Dehydrocholesterol
uv light
HO
CH 2
Vitamin D
Liver
OH
CH 2
HO
25-hydroxyvitamin D
Kidney
FIGURE 23-9 Vitamin D metabolism. Vitamin D is formed
in the skin of most animals after exposure to ultraviolet radiation.
Vitamin D can also come from the diet. It is hydroxylated
in the liver to 25-hydroxyvitamin D, and in the kidney to 1,25-
dihydroxyvitamin D, which is the active form. The production
of 1,25-dihydroxyvitamin D is normally regulated through feedback
control and the influence of parathyroid hormone (PTH)
on the activities of the 1 α -OH or 25-OH-vitamin D hydroxylase.
A fall in plasma calcium triggers the release of PTH from the
parathyroid gland, which stimulates 1 α-hydroxylase production
and leads to an increase in output. A separate hydroxylase,
which catalyzes 24,25-(OH) 2 -vitamin D 3 production, is activated
under eucalcemic and hypercalcemic states. The major sites of
action in relation to calcium homeostasis are bone and intestine.
The immune system and the pancreas are also sensitive to
changes in vitamin D status.
Normal or high Ca, normal PTH
OH
OH
Low Ca, High PTH
OH
HO
CH 2
HO
CH 2
OH
24, 25-dihydroxyvitamin D
1, 25-dihydroxyvitamin D
1, 24, 25-dihydroxyvitamin D
Calcitroic Acid
Bone
Intestine
T and B-cell functions
Pancreas
as the site of 1,25-dihydroxycholecalciferol (calcitriol or
1,25-(OH) 2 -D 3 ) production. This discovery, together with
the finding that 1,25-(OH) 2 -D 3 was in the nuclei of intestinal
cells, suggested that vitamin D was functioning in a
manner analogous to that for steroid hormones. The production
of calcitriol is normally closely regulated through
feedback control and the influence of parathyroid hormone
(PTH) on the activities of the 1 α - and 24-OH-hydroxylases.
A fall in plasma calcium triggers the release of PTH
from the parathyroid gland, which stimulates 1 α-hydroxylase
production and leads to an increase output of calcitriol
from the kidney. A separate hydroxylase, which catalyzes
24,25-(OH) 2 -D 3 production, is activated under eucalcemic
and hypercalcemic states. Whether 24,25-(OH) 2 -D 3
serves an essential function is controversial. However,
there is evidence that 24,25-(OH) 2 -D 3 is required for some
of the biological responses attributed to vitamin D ( Dusso
et al., 2005 ; Norman et al. , 2002). Norman and coworkers
(Norman et al. , 2002) have shown that hatchability in
chickens markedly improves if both 1,25-(OH) 2 -D 3 and
24,25-(OH) 2 -D 3 are administered into eggs containing viable
embryos from hens rendered rachitic (vitamin D deficient)
before egg production. The two major sites of action
of calcitriol in relation to calcium homeostasis are bone,
where it acts rapidly in concert with PTH in response to
hypocalcemia, and at the intestine, where the response time
is longer. In addition to 1,25-(OH) 2 -D 3 and 24,25-(OH) 2 -D 3 ,
more than 20 other hydroxylated intermediates and end
products have been identified. Most of these are probably
routed into elimination pathways, although some may be
potentially functional (e.g., 1,24,25-trihydroxycholecalciferol,
which has some vitamin D activity).
Calbindin, a calcium binding protein, is a major product
synthesized in intestinal cells in response to calcitriol.
Calbindin influences the movement of calcium across the
intestinal cell. Binding of calcium to this protein allows
the intracellular concentration of calcium to be elevated.
The hormone forms of cholecalciferol also stimulate the
production of the calcium, sodium-dependent ATPases,
which reside on the luminal surface of the intestinal cell.
This facilitates the vectorial movement of calcium out of
the cell into circulation. In addition, evidence also indicates
that 1,25-(OH) 2 -D 3 can stimulate secondary messenger
systems (e.g., protein kinase and adenyl cyclase-controlled
dependent messenger systems) ( Dusso et al., 2005 ).
In addition to intestinal cells, the osteoblasts of bone
are another target of vitamin D metabolites and play a
major role in short-term calcium homeostasis. In addition,