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

1282
SECTION V
HORMONES AND HORMONE ANTAGONISTS
(25-OHD, or calcifediol) and 25-OH-ergocalciferol, respectively.
25-OHD is the major circulating form of vitamin D 3
; it has a biological
t 1/2
of 19 days, and normal steady-state concentrations are 15-50
ng/mL. Reduced extracellular Ca 2+ levels stimulate 1α-hydroxylation
of 25-OHD, increasing the formation of biologically active
1,25(OH) 2
D 3
. In contrast, when Ca 2+ concentrations are elevated,
25-OHD is inactivated by 24-hydroxylation. Similar reactions occur
with 25-OH-ergocalciferol. Normal steady-state concentrations of
25-OHD in human beings are 15-50 ng/mL, although concentrations
<25 ng/mL may be associated with increased circulating PTH and
greater bone turnover.
1α-Hydroxylation of 25-OHD. After production in the liver, 25-OHD
enters the circulation and is carried by vitamin D–binding globulin.
Final activation to calcitriol occurs primarily in the kidney but also
takes place in other sites, including keratinocytes and macrophages
(Hewison et al., 2004). The enzyme system responsible for 1α-hydroxylation
of 25-OHD (CYP1α, 25-hydroxyvitamin D 3
-1α-hydroxylase,
1α-hydroxylase) is associated with mitochondria in proximal tubules.
Vitamin D 1α-hydroxylase is subject to tight regulatory controls
that result in changes in calcitriol formation appropriate for
optimal calcium homeostasis. Dietary deficiency of vitamin D, calcium,
or phosphate enhances enzyme activity. 1α-Hydroxylase is
potently stimulated by PTH and probably also by prolactin and estrogen.
Conversely, high calcium, phosphate, and vitamin D intakes
suppress 1α-hydroxylase activity. Regulation (Figure 44–5) is both
acute and chronic, the latter owing to changes in protein synthesis.
PTH increases calcitriol production rapidly via a cyclic AMP–dependent
pathway. Hypocalcemia can activate the hydroxylase directly in
addition to affecting it indirectly by eliciting PTH secretion (Bland
et al., 1999). Hypophosphatemia greatly increases 1α-hydroxylase
activity. Calcitriol controls 1α-hydroxylase activity by a negativefeedback
mechanism that involves a direct action on the kidney, as
well as inhibition of PTH secretion. The plasma t 1/2
of calcitriol is
estimated at 3-5 days in humans.
24-Hydroxylase. Calcitriol and 25-OHD are hydroxylated to
1,24,25(OH) 2
D and 24,25(OH) 2
D, respectively, by another renal
enzyme, 24-hydroxylase, whose expression is induced by calcitriol
and suppressed by factors that stimulate the 25-OHD-1α-hydroxylase.
Both 24-hydroxylated compounds are less active than calcitriol
and presumably represent metabolites destined for excretion.
Physiological Functions and Mechanism of Action.
Calcitriol augments absorption and retention of Ca 2+
and phosphate. Although regulation of Ca 2+ homeostasis
is considered to be its primary function, accumulating
evidence underscores the importance of calcitriol
in a number of other processes.
Calcitriol acts to maintain normal concentrations
of Ca 2+ and phosphate in plasma by facilitating their
absorption in the small intestine, by interacting with
PTH to enhance their mobilization from bone, and by
decreasing their renal excretion. It also exerts direct
physiological and pharmacological effects on bone
mineralization (Suda et al., 2003).
The mechanism of action of calcitriol is mediated
by its interaction with VDR. Calcitriol binds to cytosolic
HO
CH 2
PTH
Ca 2+ , phosphate
25-OHD
PTH
1, 25-(OH) 2 D
CH 2
OH
Ca 2+ , phosphate
(estrogen, prolactin)
OH
HO OH
Figure 44–5. Regulation of 1α-hydroxylase activity. Changes in
the plasma levels of PTH, Ca 2+ , and phospate modulate the
hydroxylation of 25-OH vitamin D to the active form, 1,25-dihydroxyvitamin
D. 25-OHD, 25-hydroxycholecalciferol; 1,25-
(OH) 2
-D, calcitriol; PTH, parathyroid hormone.
VDRs within target cells, and the receptor–hormone
complex translocates to the nucleus and interacts with
DNA to modify gene transcription. The VDR belongs
to the steroid and thyroid hormone receptor superfamily.
Calcitriol also exerts nongenomic effects. It is controversial
whether the presence of a functional VDR is
required for this action (Zanello and Norman, 2004).
Intestinal Absorption of Calcium. Calcium is absorbed predominantly
in the duodenum, with progressively smaller amounts in the jejunum
and ileum. Studies of Ca 2+ uptake by isolated cells reflect these differences
and suggest that elevated amounts of transport are likely due
to greater transport by each duodenal cell. The colon also contributes
to calcium absorption because ileostomy reduces absorption.
In the absence of calcitriol, calcium absorption is inefficient
and proceeds in a thermodynamically passive manner through the
lateral intercellular spaces (paracellular pathway). Calcitriol
increases the transcellular movement of Ca 2+ from the mucosal to
the serosal surface of the duodenum. Transcellular Ca 2+ movement
involves three processes: Ca 2+ entry across the mucosal surface, diffusion
through the cell, and energy-dependent extrusion across the
serosal cell membrane. Calcium is also secreted from serosal to