rem ains norm al. B on e disease associated with hepatic fail-
ure m ay be due to m alabsorption o f vitam in D , interrup-
tion o f enterohepatic circulation o f vitam in D m etabolites,
insufficient exposure to sunlight, or the need for som e v i-
tam in D m etabolite other than l,2 5 -(O H )2D for normal
bone m ineralization.
A t high doses,
(D H T ), produced
by chem ical reduction o f tachysterol (Figure 37-4), is
m ore effective than vitam in D in m obilizing bone cal-
cium and stim ulating intestinal calcium absorption. D H T
is activated by 25-hydroxylation in the liver by the sam e
en zym e system as vitam in D (Figure 37-4). U nlike 25-
(O H )D 3, 25-D H T does not require 1-hydroxylation for
activity. The antirachitic activity o f 25-(O H )D H T is ap-
parently due to its A ring being inverted relative to that
o f vitam in D. Thus, its 3/3-hydroxyl group is in approx-
im ately the sam e position as the la -h yd roxyl group o f
l,2 5 -(O H )2D . D H T is used to treat many disorders o f
vitam in D m etabolism .
Vitamin D m etabolites have been found in plants.
a disease o f cattle that graze on the plant
Solanum glaucophyllum (malacoxalon)
in South Am erica,
is characterized by calcin osis and soft-tissue calcification.
A queous extracts o f the leaves o f this and other plants
that have been used to treat urem ic bone disease contain
glycosid es o f l,2 5 -(O H )2D.
F I G U R E 3 7 - 4
Structures of 25-hydroxydihydrotachysterols [25-(OH)DHT3] and
l,25-(OH)2D3, the biologically active forms of dihydrotachysterol
, respectively. Note the similar spatial arrangement of the 3- and
25-hydroxyl groups in DHT and of the 1- and 25-hydroxyl groups in
Vitam in D toxicity (hypervitam inosis D ) can be pro-
duced in hum ans by ingestion o f 2 0 0 0 -5 0 0 0 units o f vi-
tam in D per kilogram per day for several m onths. It is
characterized by hypercalcem ia and hypercalciuria. B e-
cause serum phosphate levels are usually normal, the
C a2+ x P 0
solubility product is exceeded. E ctopic cal-
cification results and in the kidney leads to renal failure.
B ecau se excess vitam in D is stored in adipose tissue and
is released gradually, hypercalcem ia m ay persist after in-
gestion o f vitam in D has stopped. T he circulating concen-
tration o f 25-(O H )D is 1000 tim es normal, whereas that
o f l,2 5 -(O H )2D is normal or low. T hese concentrations
reflect the tight regulation o f la-h y d ro x y la se and the lack
o f regulation o f 25-hydroxylase. T he high concentration
o f 25-(O H )2D and the observation that anephric patients
can becom e intoxicated w ith vitam in D suggest that the
hypercalcem ia is caused by 25-(O H )D . In fact, 25-(O H )D
is antirachitic but is m uch less potent than 1,25-(O H )2D.
binding studies using intestinal cytoplasm ic bind-
ing proteins have show n their affinity for 1,25-(O H )2D to
be about 1000 tim es more than for 25-(O H )D . Transient
hypercalcem ia has been noted follow in g oral therapeu-
tic doses o f l,2 5 -(O H )2D , and acute vitam in D toxicity
could presum ably result from pharm acological doses o f
this com pound.
Parathyroid Hormone (PTH).
Hum ans usually have
four parathyroid glands, located behind the thyroid. They
w ere frequently rem oved during thyroidectom y, leading to
hypocalcem ia. The parenchym a o f the glands is com posed
o f ch ief cells and oxyphil cells. T he ch ief cells are more
num erous and are responsible for production o f PTH. The
oxyphil cells have no known function.
PTH is a polypeptide o f 84 am ino acids (M .W . 9,500).
is present in
the N-term inal
34-residue peptide [P T H (l-3 4 )]. R em oval o f the first
tw o residues elim inates b iological activity, even though
P T H (3 -3 4 ) binds w ell to PTH receptors.
The m R N A for PTH cod es for pre-proPTH, w hich con -
tains 115 am ino acids (M .W . 13,000). The N-term inal pre-
sequence o f 25 residues is hydrophobic and is sim ilar to
leader sequences o f other secreted proteins. It is rem oved
w ithin 1 m inute o f com pletion o f synthesis o f pre-proPTH,
leaving proPTH. During transport o f proPTH to the
G olgi apparatus for packaging into secretory vesicles, the
N -term inal hexapeptide is cleaved to form PTH. The tim e
elapsed from form ation o f proPTH to conversion to PTH
is about 1 5 -2 0 m inutes.
PTH can be secreted, sequestered in an intracellular
storage pool, or degraded w ithin the parathyroid gland.
Secretion is thought to occur by exocytosis, although the
num ber o f secretory granules is inadequate to maintain the
observed rate o f sustained release o f PTH. It appears that