DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

mucosal compartments. Thus, net calcium absorption is the difference
between the two oppositely oriented vectorial processes. The
complex mechanisms and the proteins mediating calcium absorption
are still incompletely understood (Perez et al., 2008). Evidence
implicates TRPV6 Ca 2+ channels in mediating mucosal calcium
entry in the intestine (Bianco et al., 2007). In humans, TRPV6 is
expressed in the duodenum and proximal jejunum. A calcium-poor
diet upregulates intestinal TRPV6 expression in mice (Van
Cromphaut et al., 2001). This effect is greatly reduced in VDR
knockout mice, suggesting that TRPV6 mediates calcium entry and
is vitamin D dependent.
Ca 2+ absorption is potently augmented by calcitriol. It is likely
that calcitriol enhances all three steps involved in intestinal Ca 2+
absorption: entry across mucosal brush border membranes, diffusion
through the enterocytes, and active extrusion across serosal plasma
membranes. Calcitriol upregulates the synthesis of calbindin-D 9K
and
calbindin-D 28K
and the serosal plasma membrane Ca–ATPase.
Calbindin-D 9K
enhances the extrusion of Ca 2+ by the Ca–ATPase,
whereas the precise function of calbindin-D 28K
is unsettled.
Mobilization of Bone Mineral. Although vitamin D–deficient animals
show obvious deficits in bone mineral, there is little evidence that calcitriol
directly promotes mineralization. Thus, even though VDR
knockout mice exhibit severely impaired bone formation and mineralization,
these deficiencies can be entirely corrected by a high-calcium
diet. These results support the view that the primary role of calcitriol is
to stimulate intestinal absorption of calcium, which, in turn, indirectly
promotes bone mineralization. Indeed, children with rickets caused by
mutations of the VDR have been treated successfully with intravenous
infusions of Ca 2+ and phosphate. In contrast, physiological doses of
vitamin D promote mobilization of Ca 2+ from bone, and large doses
cause excessive bone turnover. Although calcitriol-induced bone
resorption may be reduced in parathyroidectomized animals, the
response is restored when hyperphosphatemia is corrected. Thus, PTH
and calcitriol act independently to enhance bone resorption.
Calcitriol increases bone turnover by multiple mechanisms
(Suda et al., 2003). Mature osteoclasts apparently lack the VDR.
Acting by a non-VDR mechanism, calcitriol promotes the recruitment
of osteoclast precursor cells to resorption sites, as well as the
development of differentiated functions that characterize mature
osteoclasts.
Osteoblasts, the cells responsible for bone formation, express
the VDR, and calcitriol induces their production of several proteins,
including osteocalcin, a vitamin K–dependent protein that contains
γ-carboxyglutamic acid residues, and interleukin-1 (IL-1), a lymphokine
that promotes bone resorption (Spear et al., 1988). Thus the
current view is that calcitriol is a bone-mobilizing hormone but not
a bone-forming hormone. Osteoporosis is a disease in which osteoclast
responsiveness to calcitriol or other bone-resorbing agents is
profoundly impaired, leading to deficient bone resorption.
Renal Retention of Calcium and Phosphate. The effects of calcitriol
on the renal handling of Ca 2+ and phosphate are of uncertain importance.
Calcitriol increases retention of Ca 2+ independently of phosphate.
The effect on Ca 2+ is thought to proceed in distal tubules,
whereas enhanced phosphate absorption occurs in proximal tubules.
Other Effects of Calcitriol. It now is evident that the effects of calcitriol
extend well beyond calcium homeostasis. Receptors for calcitriol
are distributed widely throughout the body (Pike and Shevde,
2005). Calcitriol affects maturation and differentiation of mononuclear
cells and influences cytokine production and immune function
(Nagpal et al., 2005). One focus of research is the potential use of
calcitriol to inhibit proliferation and to induce differentiation of
malignant cells (van den Bemd et al., 2000). The possibility of dissociating
the hypercalcemic effect of calcitriol from its actions on
cell differentiation has encouraged the search for analogs that might
be useful in cancer therapy. Calcitriol inhibits epidermal proliferation
and promotes epidermal differentiation and therefore is a potential
treatment for psoriasis vulgaris (Kragballe and Iversen, 1993)
(Chapter 65). Calcitriol also affects the function of skeletal muscle,
brain (Carswell, 1997), and blood pressure (Nagpal et al., 2005).
Calcitonin
Calcitonin is a hypocalcemic hormone whose actions
generally oppose those of PTH.
History and Source. Copp observed in 1962 that perfusion of canine
parathyroid and thyroid glands with hypercalcemic blood caused a
transient hypocalcemia that occurred significantly earlier than that
caused by total parathyroidectomy. He concluded that the parathyroid
glands secreted a calcium-lowering hormone (calcitonin) in
response to hypercalcemia and in this way normalized plasma Ca 2+
concentrations. The physiological relevance of calcitonin has been
challenged vigorously: calcitonin normally circulates at remarkably
low levels; surgical removal of the thyroids has no appreciable effect
on calcium metabolism; and conditions associated with profound
elevations of serum calcitonin concentration are not accompanied
by hypocalcemia (Hirsch and Baruch, 2003). The primary interest in
calcitonin arises from its pharmacological use in treating Paget’s disease
and hypercalcemia and in its diagnostic use as a tumor marker
for medullary carcinoma of the thyroid.
The thyroid parafollicular C cells are the site of production
and secretion of calcitonin. Human C cells, which are derived from
neural crest ectoderm, are distributed widely in the thyroid, parathyroid,
and thymus. In non-mammalian vertebrates, calcitonin is found
in ultimobranchial bodies, which are separate organs from the thyroid
gland.
The calcitonin gene is localized on human chromosome 11p
and contains six exons (Figure 44–6). The primary transcript is alternatively
spliced in a tissue-specific manner. In thyroid C cells, the
calcitonin/calcitonin gene-related peptide (CGRP) pre-mRNA is
processed primarily with common exons 2 and 3 to include exon 4.
This leads to production of the 32-amino-acid peptide calcitonin,
along with a flanking 21-amino-acid peptide called katacalcin,
whose physiological significance is unknown. In neuronal cells, in
contrast, most of the calcitonin/CGRP pre-mRNA, is processed to
exclude exon 4, resulting in inclusion of exons 5 and 6 with common
exons 2 and 3, which ultimately gives rise to CGRP. This results in
the production of the 37-amino-acid CGRP. Calcitonin is the most
potent peptide inhibitor of osteoclast-mediated bone resorption and
helps to protect the skeleton during periods of “calcium stress,” such
as growth, pregnancy, and lactation. CGRP and the closely related
peptide adrenomedullin are potent endogenous vasodilators.
Chemistry and Immunoreactivity. Calcitonin is a single-chain peptide
of 32 amino acids with a disulfide bridge linking the cysteine
residues in positions 1 and 7 (Figure 44–7). In all species, 8 of the
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CHAPTER 44
AGENTS AFFECTING MINERAL ION HOMEOSTASIS AND BONE TURNOVER