section 37.1
Calcium and Phosphorus
881
HO
Vitamin D3
(cholecalciferol)
25-H y d ro x y ch o lecald fero l
[25-(O H )D ,]
1 a , 25-D ihydroxycholecaIdferol
[ 1 ,25-(O H ) D3; calcitriol]
FIGURE 37-2
Activation of vitamin D
3
by hydroxylation. Vitamin D
2
is metabolized to 1,25-(OH)2D2
(lœ,25-dihydroxyergocalciferol), its active form, by the same enzymes.
o f fortifying m ilk and m ilk products w ith vitam in D has
nearly elim inated rickets as a major disease o f infancy and
childhood in industrialized countries. The m etabolism and
biological activity o f vitam in D
2
in hum ans are identical to
those o f vitam in D 3. For this reason, the subscripts 2 and
3 are usually om itted from vitam in D and its m etabolites
except w hen it is important to distinguish D
2
from D 3.
Several other sterols that differ from ergocalciferol and
cholecalciferol only in the side chain can be converted to
antirachitic com pounds by ultraviolet irradiation.
The discovery and elucidation o f m odifications to vita-
m in D that render it b iologically active represented a m a-
jor advance in understanding how this vitam in functions
and explained the lag betw een adm inistration o f vitam in D
and its effect on serum calcium (Figure 37-2). V itam in D
and its m etabolites are transported in the circulation bound
m ainly to
vitamin D-binding protein
(G c-protein, tran-
scalciferin; M .W . 56,000), an a-globu lin . Serum norm ally
contains 5 0 0 -5 5 0 /zg/m L
( 6
x 10
- 6
m ol/L ) o f this pro-
tein. This concentration is unchanged in disorders o f cal-
cium hom eostasis. Vitam in D -binding protein, album in,
and a-fetoprotein are all structural hom ologu es. T hey are
all synthesized in the liver, belon g to the sam e m ultigene
fam ily, and probably arose from duplication o f the sam e
ancestral gene.
In
the
liver,
vitam in
D
is
hydroxylated
to
25-
hydroxy vitam in D [25-(O H )2D ], the principal circulating
m etabolite o f vitam in D. In the kidney, hydroxylation at
position 1 yields l,2 5 -(O H )2D . This m etabolite has the
highest sp ecific activity o f the naturally occurring m etabo-
lites. 24,25-(O H )2D is also synthesized by renal m itochon-
dria and in other tissues in relatively large am ounts in an-
im als w ith adequate intake o f vitam in D , calcium , and
phosphorus. T h ese conditions are opposite to those that
favor synthesis o f l,25-(O H )2Ö . C onsequently, the serum
concentration o f 24,25-(O H )2D varies inversely w ith that
o f l,25-(O H )2D . 24,25-(O H )2D m ay be o f p hysiological
im portance, particularly in bone; patients w ith P aget’s d is-
ease have normal plasm a concentrations o f l,2 5 (O H )2D
but low concentrations o f 24,25(O H )2D . Furthermore,
patients w ith chronic renal disease or osteom alacia that
is resistant to l,25-(O H )2D show clinical im provem ent
in response to com bined therapy w ith l,25-(O H )2D and
24,25-(O H )2D . Other m etabolites o f vitam in D have been
characterized but have little or no activity in the usual
assays.
There are tw o hepatic vitam in D 25-hydroxylases,
the major one in the m itochondria and the other in the
sm ooth endoplasm ic reticulum (Figure 37-2). B oth re-
quire N A D P H and m olecular oxygen . The m icrosom al
en zym e appears to be a P -450 m ixed-function oxidase.
25-H ydroxylase activity also occurs in intestine, kidney,
and lung. 25-H ydroxylase is apparently regulated only
by availability o f its substrate, leading to a high plasm a
concentration o f 25-(O H )D and a low concentration o f
vitam in D.
25-(O H )D -la-h yd roxylase is found in the inner m ito-
chondrial m em brane o f the cells lining the proxim al con -
voluted renal tubules. It is a m ixed-function oxid ase that
requires m olecular oxygen , a flavoprotein, a ferredoxin,
and a cytochrom e P -450 for activity. It is inhibited by car-
bon m onoxide. Placental tissue contains la -h y d ro x y la se
activity, as do cultured bone cells and m acrophages. This
finding is o f questionable im portance under m ost circum -
stances, however, since l,2 5 -(O H )2D is not present in sig-
nificant am ounts in nonpregnant, nephrectom ized anim als,
