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Inggris Biokim
Inggris Biokim
loomis (1967) popularized the theory that melanin pigmentation in humans evolved
to protect people who lived at or near the equator from producing excessive,
intoxicating amounts of vitamin D3. he further speculated that as peoples migrated
north and south of the equator they lost their skin pigmentation in order to promote
an adequate amount of vitamin D3 synthesis in their skin to protect their bones
from developing rickets and osteomalasia. melanin is an excellent sunscreen that
absorbs the ultraviolet radiation from sunlight. therefore, melanin competes with 7-
DHC in the skin for the UVB photons. as a result, increased skin pigmentation
decreases the production of previtamin D3 in the skin (clemens et al., 1982).
we have previously found that blacks with very dark skin pigmentation require
tenfold longer exposure to simulated sunlight to make the same amount of vitamin
D3 in their skin as does a light-skinned white (clemens et al., 1982). because
sunlight prevents an excessive production of either previtamin D3 or vitamin D3 in
the skin by causing the photodegradation of excessive amounts of these
compounds, it is unlikely that melanin pigmentation evolved for the purpose of
preventing vitamin D3 intoxication due to excessive exposure to sunlight of peoples
who live near the equator. it is, however, intriguing to consider the possibility that
skin pigmentation gradually disappeared in peoples that migrated north and south
of the equator in order to promote an adequate production of vitamin D3 in the skin.
this concept remains a theory and has not been proved. however, it should be noted
that blacks who line in northern europe,where food is not fortified with vitamin D as
it is in the united states, do not suffer from a higher incidence of rickets and
osteomalacia caused by vitamin D deficiency when campared with northern
european whites.
The time of day, season of the year, and latitude have dramatic effects on the
amount of solar UVB radiation that reaches the earths surface. In winter, vitamin
producing UVB photons pass through the ozone layer at an oblique angle and are
absorbed by the ozone in great numbers. More UVB photon are able to penetrate
the ozone layer in the spring, summer, and fall months because the sun is directly
overhead. At latitude 42o N (Boston), sunlight is incapable of producing vitamin D3
in the skin from November through February. Ten degrees north of boston (52 o N,
edmonnton, Canada), this period is extended to include October and march (fig.27-
2) (webb et al.,1988).
Exposure to sunlight at lower latitudes such as iin los angles (24 o N), Puerto rico (18o
N), and Buenos aires (34o S), results in the cutaneous production of vitamin D3
during the entire year. During the summer in boston, exposure to sunlight from the
hours of 7 A.M to 5 P.M. estern standard time (EST) result in sufficient UVB photons
to produce previtamin D3 in the skin. I the spring and fall months, vitamin D
production commences at approximately 9 A.M an cease after 3 P.M EST.
Aging affects many different metabolic processes. Therefore, it is not surprising that
aging also decreases the capacity of human skin to produce vitamin D3. Aging
decreases the concertation of 7-DHC n the epidermis and thereby reduces the
capacity of the skin to produce vitamin D3 by approximately 75% by age 70 years
compared with younger adults (fig. 27-3) (holick et al., 1989).
The pulic is now very much aware that chronic excessive exposure to sunlight can
increase the risk of skin cancer and cause photoaging of the skin. This has led to the
general recommendation thet people of races that sunburn should always wear a
sunscreen before going outdoors (Gilchrest, 1993). Commercial sunscreens work by
bsorbing solar UVB radiation, and some product s also absorb some or all of the
solar ultraviolet A (320 to 400 nm) radiation. Thus, sunscreens act like melanin and
prevent these high-energy photons from having adverse effects on the skin.
Sunscreen use has been proved to decrease the risk of some forms of skin cancer,
including squamous cell carcinoma, and to reduce photodamage that causes
photoaging of the skin. However, since the solar radiation that is responsible for
causing the damaging effects to the skin is the same radiation that causes the
cutaneous production of vitamin D3. It is not surprising that the topical application
of a sunscreen can diminish or completely prevent the vitamin D3 production in the
skin. When a young adult expose the whole body to simulated sunlight that causes
a minimal sunburning (1 minimal erythernal dose; MED), the amount of vitamin D3
that is produced in the skin and enters the circulation is equivalent to taking
between 10.000 and 25,000 IU of vitamin D orally.
When healthy young adult volunteers applied a sunscreen preparation with aa sun
protection factor of 8 (SPF-8) before being exposed to a whole body dose of 1 MED
of simulated sunlight, plasma levels of vitamin D did not rise above the baseline
value (fig. 27-4). To further investigate the impact of sunscreen use on the
cutaneous production of vitamin D3, 10 volunteers who wore typical clothing for a
summer day (short-sleeved blouse or shirtand short) topically applied a sunscreen
with an SPF of 25 only to the face or to unclothed ares with the exception of the
face. Twenty-four hours after exposure to 0.9 MED of simulated sunlight, a small in
crease in the circulating concentration of vitamin D3, from 3.0 1.0 (mean SEM)
to 4.4 + 1.0 ng/mL of serum, was noted in the volunteers who exposed only their
faces. When the face was covered and the arms and legs were exposed there was a
significant increase in the serum vitamin d level: from 1.9 0.3 to 0.8 ng/mL.
Clothing absorbs most ultra violet radiation; therefore, covering the sskin with most
types of clothing will prevent the cutaneous production of vitamin D3(matsuoka et
al., 19920 (fig. 27-5). People of cultures such as Bedouins living in the negev desert,
who are require to have most of the skin surface covered by clothing, are prone to
develop vitamin D deviciency (taha et al. 1984).
It is recommended that children and young adults always wear a sunscreen with an
SPF of at least 15 to prevent the consequences of chronic excessive exposure to
sunlight. There is no need to be concerned about the effet of sunscreen use on
preventing the cutaneous production of vitamin D3 in this population because it is
unlikely that they will always wear a sunscreen or use the proper amount of the
agent before going outdoors. However , there is reason for concern with regard to
elderly people, who often depend on sunlight for their vitamin D requirement . if
they limit their outdoor activities ad apply a sunscreen properly before going out,
they can substantially reduce or even prevent the production of vitamin D3 and
develop a subclinical vitamin D deficiency (holick, 1994).
The major natural sources of vitamin D are fatty fish like mackerel and salmon and
fish oils, including cod and tuna liver oils. The major dietary sources of vitamin D are
food fortified with vitamin D2 or D3. Milk has been fortified with vitamin D in the
united states since the 1930s. more recently, some cereals and breads have been
fortified with vitamin D. other dairy products, including ice cream, cheeses, and
yogurt, are not fortified with vitamin D.
The vitamin D content in milk, however, is variable. Several recent studies suggest
that in the united states and western Canada, up to 80% of samples tested did not
contain between 400 and 600 IU/quart (10 an 15 g/quart) of vitamin D. almost 50%
of the samples did not contain 50% of the vitamin D stated on the label, and
approximately 15% of the skim milk sample contained no detectable vitamin D
(holick,1994). Multivitamin preparation containing vitamin D were found to be a
good source of vitamin vitamin D and contained between 400 and 600 IU (10 an 15
g/quart) of vitamin D per tablet; pharmaceutical preparations labeled as 50,000 IU
(1250 g) of vitamin D2 contained the stated amount 10%. Although the 1980
and 1989 RDAs for vitamin D were set at 5 g/day for adults, there is mounting
evidence that in the absence of sunlight the actual requirement for vitamin D in
adults may be as much as 15 to 20 g/day (dawson-hughes et al., 1991 ; holick,
1994). This is now reflected in the recently released dietary reference intakes for
vitamin D (institute of medicine, 1997). Although a new RDA was not established,
the adequate intake (AI) for vitamin D was set at 5 g/day for individuals 50 years of
age and younger but at 10 g/day for adults 51 to 70 years of age and at 15 g/day
for adults more than 70 years of age.
Vitamin D deficiency causes rickets in children (holick, 1994). Before the epiphyseal
plates close, vitamin D deficiency causes a disorganization and hypertrophy of the
chondrocytes at the mineralization front as well as a mineralization defect,resulting
in short stature and bony deformities that are characteristic of vitamin D deficiency
rickets (fig. 27-6). In adults the epiphyseal plates are closed, thereby preventing
many ao the bony deformities seen in rachitic children. Vitamin D deficiency in
adults causes osteomalacia. Osteomalacia is a very significant metabolic bone
disease, especially in elderly people. Adults with vitamin D deficiency have a
mineralization defect in the skeleton that results in poor mineralization of the
collagen matrix (osteoid). Although this does not cause bony deformities, it can
cause severe osteopenia (a decrease in the opacity of the skeleton a seen by x-ray).
This mineraliation defect can lead to increased risk of sskeletal fractures (aaron et
al., 1974). In addition, for unexplained reasons osteomalacia can also cause
localized or generalized, unrelenting deep bone pain.
There is ample clinical evidence that increasing dietary calcium intake to at least
1000 mg/day, along with supplementation of at least 10 to 10 g of vitamin D
daily,will decrease vertebral and nonvertebral fractures and increase bone mineral
density (chapuy et al., 1992). During the winter in new England, when sunlight loses
its ability to produce vitamin D3 in the skin, there is marked loss of bone mineral
density of the hip and spine that is related to a decrease in circulating levels of 25-
OH-D and an increase in PTH levels (fig.27-8) (rosen et al., 1994).
In the body, vitamin D undergoes two hydroxylation reactions that convert it to the
biologically active form 1,25-dihydroxyvitamin D [1,25(OH)2D]. this active form of
vitamin D acts on target tissues, especially intestine and bone. It acts to regulate
calcium absorption and bone mineral mobilization in order to maintain calcium
homeostasis.
Metabolism
Vitamin D2 and vitamin D3 that are used to fortify foods are ingested, mixed with
other lipids, up by enterocytes, and incorporated into chylomicrons are released by
the enterocytes and enter the lymphatic system, which drains into the venous blood
stream. Ultimately, this vitamin D (in chylomicron remants) reaches the liver, where
it is hydroxylated and again enters the circulation bound to vitamin D-binding
protein. Vitamin D3 that is synthesized in the skin enters the circulation and is
bound to the vitamin D-binding protein.
Both vitamin D2and vitamin D3 in the circulation are taken up by the liver and
hydoxylated on carbon 25 to produce 25-OH-D (see fig.27-7). 25-OH-D is the major
circulating form f vitamin D, and it is present in the circulation bound to the vitamin
D-binding protein. It is 25-OH-D that is measured in te blood to determine the
vitamin D status of a patient. The hepatic vitamin D 25-hydroxylase is not tightly
regulated; therefore, any increase in vitamin D intake or in the cutaneousproduction
of vitamii D3leads to an increase in the circulating concentration of 25-OH-D. that is
the reason why 25-OH-D is so valuable as a marker for determining the vitamin D
status of a patient. Low or undetectable circulating concentration of 25-OH-D are
diagnostic of vitamin D deficiency, and 25-Oh-D levels that are two to three times
the upper limit of the normal range (normal range, 10 to 55 ng/mL of serum) are
diagnostic for vitamin D intoxication (holick et al., 1994).
Once 25-OH-D is made, it enters the circulation, and most of it is bound to the
vitamin D-binding protein. The unbound form of 25-OH-D enters the kidney tubular
cells, where it is hydroxylated on carbon 1 to form 1,25(OH) 2D (see fig.27-7). 1,25
(OH)2D in considered to be the biologically active form of vitamin D that is
responsible for carrying out most if not all of the biological functions of vitamin D.
the major function of 1,25(OH)2D is to increase the efficiency of intestinal calcium
absorption, thereby increasing the utilization of dietary calcium (see fag.27-7).
1,25(OH)2D can increase the efficiency of intestinal calcium absoption from a basal
level of 20% to 300% up to 80%.
The major factor that regulates the metabolism of 25-OH-D to 1,25(OH) 2D is PTh
(see fig. 27-6). The exact mechanism by which PTH stimulates the kidneys
production of 1,25(OH)2D is not well characterized. However, there is evidence that
the hypophosphatemic effect of PTH on the kidney may be responsible for
increasing the renal production of 1,25(OH) 2D (holick et al., 1994). Indeed,
hypophosphatemia and hyperphosphatemia are associated with increased and
decreased circulating concentrations of 1,25(OH) 2D, respectively. A variety of other
hormones associated with growth and development of the skeleton or calcium
regulation, including growth hormone and prolactin, indirectly increase the renal
production of 1,25(OH)2D.
It is recognized that elderly people often lose their ability to adapt to a low calcium
diet by increasing their efficiency of intestinal calcium absorption (Ireland and
fordtran, 1973). Although the exact mechanism is not fully understood, there is
evidence that the ability of the kidney to upregulate the production of 1,25(OH) 2D
by PTH is no longer operative (slovik et al., 1981; riggs et al., 1981).
Although the kidney is the major site for 1,25(OH) 2D production, during pregnancy
the placenta also has the capacity to make it. This apparently is important during
the last trimester of pregnancy, when circulating levels of 1,25(OH) 2D are increased
to enhance the efficiency of intestinal calcium absorption of the mother to meet the
increased need of the fetus for calcium ti mineralize its skeleton.
There is mounting scientific evidence that other cells have the capacity to produce
1,25(OH)2D. however, it is believed that the local production of 1,25(OH) 2D is used
in an autocrine or paracrine manner and does not ccintribute to the circulating
concentration of 1,25(OH)2D. although the exact biological function of 1,25(OH) 2D in
tissues not responsible for calcium metabolism, such as circulating monocytes, skin
cells, and bone cells, is not well understood, it is recognized that 1,25(OH) 2D is a
potent inhibitor of cellular proliferation and a sstimulator of differentiation (hollick,
1994).
Biological functions of 1,25-dihydroxyvitamin D
Mature osteoblast in the bone possess vitamin D receptors and are responsive to
1,25(OH)2D. 1,25(OH)2D increase the expression of alkaline phosphatase,
osteopontin, and ostecalcin, as well as a variety of cytokines in the cells. It is likely
that 1,25(OH)2D plays an important role in the bone remodeling process. However,
1,25(OH)2D does not directly induce bone to mineralize. Instead, 1,25(OH) 2D
promotes the mineralization of osteoid laid down by osteoblast by maintaining
extracellular calcium and phosphorus concentrations within the normal
supersaturating range, which results in the passive deposition of calcium,
hydroxyapatite into the bone matrix.
Metabolism of 1,25-dihydroxyvitamin D
One 1,25(OH)2D enters the cells, it eventually finds its way to the nucleus,
where it is boundto its VDR. The VDR+1,25()H)2D complex, in turn, binds a retinoic
acid x-receptor (RXR) to form a heterodimeric complex (Pixe, 1991; Darwish and
DeLuca, 1993). This heterodimeric complex interacts with a specific vitamin D-
responsive element (VDRE) within the DNA. The DNA-binding motif for VDR, which is
present in the N-terminal part of the molecule, contains two zinc finger motifs that
interact with the DNA in the VDRE (Fig.27-9). The VDRE is composed of two
tandemly repeated hexanucleotide sequence separated by three base pairs. This
interaction ultimately leads in osteoblast are to an increase or a decrease in the
transcription of the vitamin D-responsive genes and a change in the rate of
synthesis of new mRNAs.
Vitamin d3 that is produced in the skin is stored in the body fat; therefore, the
vitamin d3 that is produced in the spring, summer, and fall can be stored and is
available during the winter when the sun is incapable of producing vitamin d3 in the
skin. This is the reason why children and the most adults do not become vitamin d-
deficient during the winter month in far northern and southern latitudes. Because a
topical application of a sunscreen can essentially prevent the producition of vitamin
d3 in the skin, people who wish to stay outdoors for long periods of time should be
exposed only to suberythermal amounts of sunlight for their vitamin d3 and then
apply a sunscreen with a SPF of 15 or greater to prevent the consequences of
chronic excessive exposure to sunlight. Children and young adults should always
wear a sunscreen before going outdoors to help. Prevents skin demage and skin
cancer. Because children and young adults will not always wear a sunscreen over all
sun-expoosed areas, they are still able to produced enough vitamin D from sun
exposure to satisfy their bodys requirement.
Although milk, some cereals, and bread products may contain vitamin D, this
is highly variable and shouls not be depended on as the only source of the vitamin.
A multivitamin tablet that contains 10 (400 IU) of vitamin D is an excellent source
and will help maintain circulating concentrations of 25-OH-D. However, in the
absence of any sunlight, a multivitamin may not be adequate to maintain normal
vitamin D status (Holick< 1994). Adults 51 years and older who have little exposure
to sunlight likely require at least 10 to 15 g of vitamin D daily to satisfy the bodys
requirement. Vitamin D deviciency can be corrected by administering an oral dose
of 500,000 IU (1250g) vitamin d2 once a week for 8 weeks. The serum 25-OH-D
level can be expected to increase from less than 15 ng/mL. This treatment will
maintain a normal vitamin D status for at least 2 to 4 month. After the 8 weeks,
patients can be placed on a multivitamin containing 400 IU (10 g) of vitamin D,
which shouls help maintaince their vitamin D status. An adequate source of calcium
in combination with vitamin D from sunlight and/or a multivitamin containing
vitamin D is essential for guaranteeing a healthy skeleton throughout life