![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Departments of Pathobiology and Laboratory Medicine, University of Toronto and Mount Sinai Hospital, Toronto, Ontario, M5G 1X5 Canada
2To whom correspondence should be addressed.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
-hydroxylase was lower
(P < 0.01) and 25(OH)D-24-hydroxylase was higher
(P < 0.05). Higher 25(OH)D concentration was
related to proportionally lower 1,25(OH)2D at every calcium
intake, indicating greater tissue sensitivity to
1,25(OH)2D. We conclude suppression of
1,25(OH)2D and PTH, and higher renal VDR mRNA and
24-hydroxylase did not involve higher free 1,25(OH)2D
concentration or a first pass effect at the gut. Thus, 25(OH)D or a
metabolite other than 1,25(OH)2D is a physiological,
transcriptionally and biochemically active, noncalcemic vitamin D
metabolite.
KEY WORDS: • vitamin D • calcium • adaptation • parathyroid hormone • rats • transcription
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
, Heaney et al. 1997
,
Reasner et al. 1990
). In humans, intestinal calcium
absorption agrees more closely with serum 25(OH)D than with
1,25(OH)2D levels (Bell et al. 1988
,
Francis et al. 1983
, Reasner et al. 1990
). Furthermore, an inverse relationship between circulating
25(OH)D levels and parathyroid hormone (PTH) has been recognized for
years in humans. As a result, the clinical definition of
hypovitaminosis D has changed dramatically, to the point where serum
25(OH)D levels in excess of 100 nmol/L are seen as desirable
(McKenna and Freaney 1998
).
For rats, Brommage and DeLuca (1985)
argued that there is no functional
role for any vitamin D metabolite, other than 1,25(OH)2D.
Later, Sandgren and DeLuca (1990)
showed that when normocalcemic,
vitamin D-deprived rats are given replacement amounts of
ergocalciferol, 1,25(OH)2D receptor (VDR) levels in kidney
double, based on an immunoassay for VDR. The issue of which vitamin D
metabolite may have caused the increase in VDR was not addressed, but
other work shows that if 1,25(OH)2D is upregulated
physiologically due to dietary calcium restriction, it does not
increase VDR (Goff et al. 1990
). There has been no
follow-up to investigate the in vivo implications of how serum
levels of vitamin D metabolites, PTH, or indices of calcium metabolism
might have responded to the increase in VDR that Sandgren and DeLuca (1990)
demonstrated at the molecular level.
Hormone receptor levels generally correlate with tissue responsiveness
to hormone (Bamberger et al. 1996
, Meyer and Schmidt 1997
). In ovariectomized rats, estrogen raises VDR
levels in the intestine, and the intestinal responsiveness to
1,25(OH)2D increases (Liel et al. 1999
). In
rats fed conventional diet, serum 1,25(OH)2D levels
correlate inversely with 25(OH)D levels (Vieth et al. 1995
). This reflects a suppression of 1,25(OH)2D
that may be explainable by higher tissue VDR levels. Here we examined
the effects of nutritionally moderate differences in vitamin D supply,
to verify the results of Sandgren and DeLuca (1990)
at the level of VDR
mRNA, and to characterize the in vivo implications of VDR upregulation
on how rats adapt to changes in dietary calcium.
We also addressed the question of whether it makes any difference from
which route the calciferol is acquired (through the skin or the gut) by
administering calciferol by either gastric or dermal routes. This was
done because results obtained with orally administered vitamin D may
reflect an unnatural situation. For most mammals, including humans and
rats, the skin is a physiological route of entry of vitamin D. Haddad et al. (1993)
showed that orally acquired vitamin D is absorbed with
chylomicrons and taken up quickly by liver metabolism, while dermally
acquired vitamin D is bound to vitamin D binding protein, and
metabolized gradually (Haddad et al. 1993
). We asked
whether the unexpected findings of VDR upregulation (Sandgren and DeLuca 1990
), and suppression of 1,25(OH)2D
likely associated with it (Vieth et al. 1995
), were
attributable to the nonphysiological way the vitamin D was administered
in those studies. Artifacts with oral treatments could have been due to
chemical or enzymatic modification of the vitamin D in the gut, or due
to first-pass action at the target organ, the intestine.
|
METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
An animal-care committee at the University of Toronto had approved the protocols and procedures used. For the first experiment, 14 male Wistar rats (Canadian Breeding Laboratories, Montreal, Canada) initially weighing 214 (±5) g wt were fed conventional diet, (Rodent Laboratory Chow, Ralston Purina Co., St. Louis, MO), which contained 1 g/100 g of elemental calcium, and vitamin D3, 4.5 IU/g (0.3 nmol/g). During the 3 wk they were maintained, they consumed an average of 25 g diet/d, (7 nmol/d vitamin D from diet). Half of the rats were supplemented with another 18 nmol/d vitamin D in ethanol.
For expt. 2, male Wistar rats, initially 120–130 g, were fed a 0.01%
calcium, 0.7% phosphate diet that was vitamin D-deficient (Teklad
Test Diets, Madison, WI) (Table 1
) for 1 wk to deplete vitamin D levels (Vieth et al. 1987
). For the next 3 wk the rats were fed the vitamin
D-deficient diet, supplemented to 0.5% elemental calcium (as
calcium carbonate powder, USP). The rats were divided into four vitamin
D-treatment groups: i) supplemented once weekly with
1.5 nmol of calciferol (0.2 nmol/d); ii) once every 2nd
d with calciferol to provide 2 nmol/d; and iii) every
2nd d with calciferol to provide 20 nmol/d. The preceding groups all
received the calciferol through an infant feeding tube directly into
the gut. One group, iv), received its calciferol in
ethanol, applied onto a shaved patch of skin on its back, this was done
every 2nd d to provide calciferol at 20 nmol/d (40 nmol calciferol per
80 µL ethanol application). The volume of each dose of calciferol
given was adjusted so that the stated doses are per 250 g body
weight. After the 3-wk preparation period, the rats ranged in weight
from 350 to 424 g, with no weight differences among the groups.
Over the next 3 wk while maintaining the described calciferol dosing
regimens, diet calcium content was changed weekly between 0.01 and 1.5
g/100 g diet. In each week, blood was obtained at d 0 (the day of, but
just prior to, the change in diet calcium), and d 1, 3 and 7 after the
change in calcium intake. During wk 1, 0.5 mL of blood was taken on the
first two of these days and anticoagulated with heparin, the cells were
isolated and resuspended in normal rat plasma and reinjected into the
femoral vein (Fox 1992
). This procedure resulted in an
unacceptable mortality rate over the following day that was probably
due to emboli in the reinfused blood. For the subsequent samplings,
only 0.2–0.3 mL of blood was taken by bleeding from the tail into
precalibrated microcentrifuge tubes. In this way, a total of <2 mL of
blood was taken that we did not replace, that is, less than or equal to
10% of the blood volume. Samples of daytime urine were collected into
microfuge tubes that were fastened to stainless steel metabolic
collection funnels designed to hang under the wire cages. The cages and
funnels were rinsed with 0.1 mol/L of hydrochloric acid prior to each
collection to remove calcium. To eliminate contamination of the urine
with diet, stool or water, the rats were placed into these separate
cages only during the urine-collection period, until about 1 mL of
urine was present in the microfuge tube; this was typically within 5
min to 1 h.
|
1,25(OH)2D in serum was measured by calf-thymus
receptor-binding assay after initial purification of
1,25(OH)2D with C18-OH cartridges (Hollis and Kilbo 1988
). For the serum volumes that were minimal, serum was
measured out in 50-µL increments, and the final result was adjusted
for the volume of sample analyzed. To measure 1-hydroxylase in renal
mitochondria, the incubation was as described previously, except the
substrate was 20 µmol/L of nonradioactive 25(OH)D. The assay was
stopped by addition of 2.5 mL of methanol. To monitor recovery of
1,25(OH)2D, 33 Bq/mL of
[3H]-1,25(OH)2D (Amersham, Oakville, Ontario,
Canada) were added in 50 µL of ethanol prior to further extraction
with two additions of 1.25 mL of methylene chloride. The methylene
chloride layer was taken and evaporated to dryness, redissolved in
hexane/isopropanol/methanol (90:9:1) for purification by HPLC,
Zorbax-sil column. The material eluting as 1,25(OH)2D
was evaporated and redissolved in acetonitrile/water for further
purification with C18-OH cartridges and quantitation by thymus receptor
assay, as described for serum. Renal 24-hydroxylase was measured by
incubating mitochondria with [3H]-25(OH)D as substrate
(Vieth and Fraser 1979
). Vitamin D-binding capacity
was measured, based on the specific uptake of
[3H]-25(OH)D3 by rat serum, involving the removal of
nonspecifically bound [3H]-25(OH)D with charcoal (Vieth 1994
). To measure 25(OH)D, 0.2 mL of serum was spiked
with 33 kBq/L with 25(OH),26,26[3H]-vitamin D (0.74
TBq/mmol; Amersham) and treated with 1 mL of acetone. Precipitated
proteins were removed by centrifugation, and the supernatant was
removed and evaporated to dryness under nitrogen. The calciferol
metabolites were redissolved with hexane and extracted with cartridges
(Vieth et al. 1995
). In short, material eluting at the
positions of authentic 25(OH)D was measured with competitive
protein-binding assay against standards of crystalline 25(OH)D that
had been purified by HPLC and quantified, based on spectral absorbance
at 265 nm, assuming 18,300 AU/(mol/L). Urinary pyridinoline bone
collagen crosslinks were measured by HPLC following hydrolysis in
hydrochloric acid (Eyre et al. 1984
) except that an
internal recovery marker (Metra Labs, Mountain View, CA) was
incorporated (Pratt et al. 1992
) prior to initial
extraction with cellulose cartridge in preparation for HPLC. Other
biochemical measures were made using routine methods established for
the Kodak Ektachem 700, dry-chemistry slide system (Rochester, NY).
PTH was measured with the rat PTH (IRMA) kit from Nichols Institute
Diagnostics (San Juan Capistrano, CA), which has a within-run CV of
5%.
Northern blot analysis of rat kidneys.
Total RNA was isolated from kidneys of control and treated rats using
TriZol (Gibco BRL, Burlington, Ontario, Canada) according to the
protocol provided by the manufacturer. This was electrophoresed on
formaldehyde agarose gels and capillary-transferred to a positively
charged nylon membrane (Boehringer Mannheim, Laval, Quebec, Canada)
using 20XSSC (Sambrook et al. 1989
). RNA was then
crosslinked to the membrane by exposing it to ultraviolet light in a
Stratalinker (Strategene, La Jolla, CA). Rat VDR cDNA (2.1 kbp EcoR1
fragment in plasmid pSG5) was kindly provided by Dr. Geoff Hendy (Royal
Victoria Hospital, Montreal, Canada). Rat VDR and GAPDH cDNA were
labeled with the digoxygenin-dUTP using the DIG-high prime DNA
labeling kit (Boehringer Mannheim). Hybridization, washing and
detection were performed using a DIG Easy Hyb and Detection Starter Kit
with the conditions provided by the manufacturer (Boehringer Mannheim).
Intensities of the VDR mRNA and GAPDH mRNA signals were read with a gel
scanner, and VDR mRNA signal normalized to the GAPDH mRNA.
Statistical analyses and calculations.
ANOVA was used to identify significant differences among the means of the four groups, and if there was evidence of differences, the Tukey-Kramer multiple-comparison test was carried out (This was with the SPSS 8.0, SPSS Chicago, IL). Furthermore, repeated measures ANOVA was used for each group of rats to compare 1,25(OH)2D levels across the days of a given diet treatment, to determine whether a plateau level had been attained. This was done by carrying out ANOVA sequentially, starting from the last day of a period of diet treatment, and working toward the earlier days until ANOVA indicated statistical variability. All statistical P-values are two-tailed unless one-tailed based on a priori expectation, as indicated.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
). The level of VDR mRNA (VDR mRNA relative to GAPDH mRNA) in kidney
correlated inversely with serum 1,25(OH)2D (Fig. 1
, r = -0.714, P = 0.006). This was a
stronger relationship than that between VDR mRNA and 25(OH)D
(r = 0.527, P = 0.032, in the expected
one-tail direction).
|
|
). Application of vitamin D to shaved rat skin proved to be an effective
way to provide vitamin D. All groups differed from one another in serum
25(OH)D. Renal 1-hydroxylase was suppressed and renal 24-hydroxylase
was increased by vitamin D nutrition. 1-Hydroxylase in the group
with the lowest 25(OH)D concentration was significantly higher than in
either of the two groups with the highest 25(OH)D. 24-Hydroxylase
differed significantly between the groups with the lowest and highest
25(OH)D. There were no significant differences among any of the groups
in serum calcium, inorganic phosphate, alkaline phosphatase or vitamin
D binding protein, or in weight gain.
|
and
3
. In all groups, urinary pyridinoline fluctuated, but its changes did
not coincide with changes in dietary calcium. At no time were there
differences in pyridinoline excretion due to the vitamin D treatment
(Fig. 2)
. Deoxypyridinoline was also measured, but the results are not
presented since they were similar to those for pyridinoline. The
urinary calcium/creatinine ratio varied in direct relation to dietary
calcium –so much so mean calcium/creatinine molar ratios approximated
the numerical values for grams of calcium/100-g diet (upper panels of
Fig. 3
). Despite minor variations among the groups, urinary
calcium/creatinine ratios did not differ significantly.
|
|
. Within each group of rats, after every change in diet
calcium, there was no difference between the 1,25(OH)2D
levels of d 3 and d 7. There was also no difference when results for
the two 20 nmol/d groups were pooled and compared to the pooled results
of the lower vitamin D intake groups. After a change in diet calcium,
the 100-fold range of vitamin D nutrition (from 0.2 to 20 nmol/d) had
no effect on the rate at which 1,25(OH)2D reached new set
points.
Higher vitamin D nutrition had a consistent suppressive effect on
1,25(OH)2D concentrations (Fig. 3
, lower panels). Because
of the sample size per group and the low statistical power of ANOVA to
detect individual differences, the differences in
1,25(OH)2D were not consistently significant for the
single-day comparisons among all four groups. To overcome this, we
pooled 1,25(OH)2D levels of the 14 rats provided vitamin D
at 20 nmol/d to compare with the 14 rats given 0.2 or 2 nmol/d. In
those given 20 nmol/d, 1,25(OH)2D levels were lower
(P < 0.05) on every day of the protocol except on the
three sampling days when the rats were fed the 1.5 g of
calcium/100-g diet. Furthermore, for each rat, the log of serum
1,25(OH)2D during calcium deprivation (average of levels on
d 3 and d 7 of weeks fed 0.01 g/100 g) was subtracted by the log of
serum 1,25(OH)2D during calcium repletion (average of
baseline and d 3 and d 7 of the week fed on 1.5 g/100 g). This was done
to reflect the amplitudes of the log changes shown for the groups in
Figure 3
. There was no significant difference in these log or ratio
changes in 1,25(OH)2D either by ANOVA among all four groups
(P = 0.67), or by t test comparing the
pooled 20 nmol/d groups vs. the pooled rats given 0.2 or 2 nmol/d of
vitamin D (P = 0.28)
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
. These
changes were accompanied by an increase in the VDR mRNA level in
kidneys. This agrees with results of Sandgren and DeLuca (1990)
who
showed that vitamin D supply increases renal VDR as measured by
immunoassay (Sandgren and DeLuca 1990
). Conventional
theories of calcium regulation predict that lower levels of both
1,25(OH)2D and PTH will lower serum calcium concentrations,
and lessen urine calcium excretion. Because these other parameters were
not affected by vitamin D supply, mechanisms responding to higher
25(OH)D must have offset the reductions in 1,25(OH)2D and
PTH.
One of our aims was to find out whether moderate differences in vitamin
D supply would affect the way rats adapt to changes in diet calcium.
During the experiment, a reasonable average of 0.5% diet calcium was
maintained (Reeves et al. 1993
) but with periods of
excess and deficiency that required adaptation. The inclusion of 1 wk
with 1.5% calcium provided an additional insight about the role of
1,25(OH)2D during calcium repletion. The urinary
calcium/creatinine ratio during the period of 1.5% dietary calcium
intake averaged three times the ratio with 0.5% calcium intake. We
interpret this as evidence that renal calcium excretion paralleled
dietary calcium, and that it reflects passive intestinal calcium
absorption (Heaney 1991
). There were no differences
within any group, in 1,25(OH)2D levels during 0.5% vs.
1.5% calcium intake (Fig. 2)
. This implies that serum
1,25(OH)2D was not functioning to regulate intestinal
calcium absorption while rats were fed the calcium-replete diets.
It was during consumption of calcium-deficient diet that
differences in 1,25(OH)2D due to vitamin D supply were
largest, and this is expected if target tissue sensitivity differs.
The urinary excretion of the collagen crosslinks, pyridinoline and
deoxypyridinoline, reflects bone resorption. In rats, the crosslink
ratio with urinary creatinine adjusts for body mass and is preferable
to results with 24-h excretion (Jerome et al. 1992
).
Pyridinoline and deoxypyridinoline were not affected by calciferol
supply. This lack of a bone-marker response to diet calcium is
consistent with a previous study of PTH infusion. It took 8 d of
infusion to demonstrate a statistically higher pyridinoline/creatinine
ratio (Jerome et al. 1992
). Our reason for measuring the
crosslinks was to determine whether they were affected by the degree of
vitamin D sufficiency. The 100-fold range in calciferol supply among
our rats was maintained for a total of 6 wk. This would have been long
enough to manifest differences in the crosslinks if they existed.
Consistent with this, there were no effects of the calciferol supply on
serum calcium, phosphate or alkaline phosphatase (Tables 1
and 2)
.
Vitamin D supply influenced 25(OH)D levels and the renal hydroxylases
appropriately for the doses given. Dermal treatment produced a
marginally lower level of 25(OH)D than achieved with the equivalent
oral dose. If one uses the 25(OH)D levels of the group receiving the
lowest vitamin D intake as a reference point, the 20 nmol/d dermal dose
generated an increase in 25(OH)D that was 85% of the increase obtained
with the same dose given orally. Vitamin D intake lowered
1-hydroxylase and increased 24-hydroxylase, as expected. These
enzyme changes show that dermal and gastric vitamin D were comparable
in the rats, with minor differences attributable to lower vitamin D
absorption efficiency from the skin than the gut. There is no support
here for the hypothesis that there is some fundamental difference in
metabolism or biological effect between dermal and gastrically acquired
vitamin D (Fraser 1983
).
Dermal application of vitamin D has potential advantages over oral vitamin D intake because it obviates the need for efficient intestinal absorption, and it avoids the requirement for ultraviolet exposure to the skin while delivering vitamin D via its physiological route of entry.
In every group, the proportional increase in serum
1,25(OH)2D concentration reached within 3 d of calcium
restriction was essentially the same as the ratios of
1,25(OH)2D in previous comparisons of long-term
calcium-deficient vs. calcium-replete diets (Gray 1981
, Hughes et al. 1975
). We were unable to
detect any effects of the 100-fold range of vitamin D supply on the
speed with which 1,25(OH)2D changed in response to dietary
calcium.
Vitamin D nutrition did influence serum PTH, 1,25(OH)2D and
kidney VDR mRNA. Moderately elevated 25(OH)D suppresses
1,25(OH)2D in rats (Hsu and Patel 1990
,
Vieth and Milojevic 1995
). Sometimes, this is also the
case in humans (Bell et al. 1988
, Reasner 1990
, Reasner et al. 1990
). To explain the
phenomenon, Reasner et al. hypothesized that 25(OH)D would occupy some
receptors for 1,25(OH)2D in bone and intestine and exert
its effects on calcium metabolism even when the concentration of the
metabolite is in the normal range (Reasner 1990
). The
present results suggest another mechanism. Previous reports have
highlighted upregulation of VDR with administration of
1,25(OH)2D or its analogs and imply a positive relationship
between 1,25(OH)2D and VDR in vivo (Gensure et al. 1998
, Goff et al. 1993
, Solvsten et al. 1997
, Yao et al. 1998
). In contrast, we produced
opposite changes in VDR mRNA and 1,25(OH)2D under the
nutritionally relevant conditions of expt. 1 (Fig. 1)
. The negative
relationship is what should be expected if higher renal VDR mRNA
content results in higher tissue VDR and higher tissue sensitivity.
Higher end-organ sensitivity to 1,25(OH)2D in vivo is
consistent with the results of expt. 2, showing lower set-point
concentrations of serum 1,25(OH)2D in groups with higher
vitamin D nutrition (Fig. 3)
. These rats were adapting to dynamic
changes in diet calcium. At all vitamin D intakes,
1,25(OH)2D concentration responded to diet calcium
restriction in a proportional manner, shown by the constant offsets on
the log-scales. The further analysis which combined all rats given
20 nmol/d vs. the lesser intakes showed that serum
1,25(OH)2D concentrations were proportionally less at all
calcium intakes compared to rats given less vitamin D. This
proportionality would not occur if the constant 25(OH)D concentrations
in each group were simply competing with 1,25(OH)2D at the
VDR.
It is relevant to note that vitamin D nutrition did not affect
circulating vitamin D binding protein (DBP). Without this result, it
could have been argued that lower 1,25(OH)2D levels were
due to lower DBP levels, and a greater proportion of
1,25(OH)2D in the biologically active, "free" state
when 25(OH)D concentration was higher (Vieth 1990
).
In short, we have shown that higher serum 25(OH)D concentrations which
would have been considered of little consequence do have substantial
biological effects not attributable to a higher 1,25(OH)2D
concentration. The apparent efficacy of 1,25(OH)2D in vivo
increased with greater vitamin D nutrition. This had been implied by
the effect of vitamin D intake to increase renal VDR (Sandgren and DeLuca 1990
), which we have confirmed at the level of mRNA.
We found that higher 25(OH)D was associated with suppression of
1,25(OH)2D regardless of calcium intake, as well as
suppression of PTH concentration without effects on other variables of
mineral homeostasis. These results support views derived from clinical
studies, that 25(OH)D has mechanisms that have yet to be explained
(Heaney et al. 1997
, Rasmussen et al. 1980
, Reasner et al. 1990
). We showed that in
rats these mechanisms do not involve changes to vitamin D binding
protein or a first-pass action at the gut.
When viewed from a perspective that starts with higher vitamin D
nutrition, the results indicate that low vitamin D nutrition may bring
about a form of resistance to 1,25(OH)2D. This situation
would explain why, in humans, nutritional rickets and osteomalacia are
commonly associated with normal or increased levels of
1,25(OH)2D (Chesney et al. 1981
,
Eastwood et al. 1979
, Garabedian et al. 1983
,Rasmussen et al. 1980
)—these are not like
the low hormone levels associated with any other endocrine—deficiency
disorder. A connection between lower vitamin D nutrition and vitamin D
resistance helps to explain why the supposedly inactive compound
25(OH)D is more relevant in diagnosing nutritional rickets than is the
active hormone 1,25(OH)2D.
If the features of improved vitamin D nutrition shown here were
demonstrated for any newly synthesized compound, the compound would be
classified as a noncalcemic 1,25(OH)2D analogue (Brown et al. 1989
, Finch et al. 1999
,
Goff et al. 1993
, Koshizuka et al. 1999
).
Thus, we contend that 25(OH)D or a metabolite of it other than
1,25(OH)2D exists as a physiological and
biologically-active noncalcemic vitamin D metabolite whose effects
require further examination, particularly in relationship to studies
involving the synthetic analogs of 1,25(OH)2D.
|
FOOTNOTES |
|---|
3 Abbreviations used: 1,25(OH)2D, 1,25-dihydroxy-cholecalciferol; 25(OH)D, 25-hydroxycholecalciferol;
cholecalciferol, vitamin D3; DBP, vitamin D-binding protein; PTH, parathyroid hormone; VDR, vitamin D receptor, intracellular receptor for 1,25(OH)2D.
Manuscript received July 29, 1999. Initial review completed September 7, 1999. Revision accepted November 16, 1999.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
1.
Bamberger C. M., Schulte H. M., Chrousos G. P. Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr. Rev. 1996;17:245-261
2. Bell N., Epstein S., Shary J., Greene V., Oexmann M. J., Shaw S. Evidence of probable role for 25-hydroxyvitamin D in the regulation of human calcium metabolism. J. Bone Miner. Res. 1988;3:489-495[Medline]
3.
Brommage R., DeLuca H. F. Evidence that 1,25-dihydroxyvitamin D3 is the physiologically active metabolite of vitamin D3. Endocrine Rev 1985;6:491-511
4. Brown A. J., Ritter C. R., Finch J. L., Morrissey J., Martin K. J., Murayama E., Nishii Y., Slatopolsky E. The noncalcemic analogue of vitamin D, 22-oxacalcitriol, suppresses parathyroid hormone synthesis and secretion. J. Clin. Invest. 1989;84:728-732
5.
Chesney R. W., Hamstra A. J., DeLuca H. F. Rickets of prematurity: Supranormal levels of serum 1,25- dihydroxyvitamin D. Am. J. Dis. Child. 1981;135:34-37
6. Colodro I. H., Brickman A. S., Coburn J. W., Osborn T. W., Norman A. W. Effect of 25-hydroxy-vitamin D3 on intestinal absorption of calcium in normal man and patients with renal failure. Metabolism 1978;27:745-753[Medline]
7. Eastwood J. B., de Wardener H. E., Gray R. W., Lemann J. L. J. Normal plasma-1,25-(OH)2-vitamin-D concentrations in nutritional. Lancet 1979;1:1377-1378[Medline]
8. Eyre D. R., Koob T. J., Van Ness K. P. Quantitation of hydroxypyridinium crosslinks in collagen by high- performance liquid chromatography. Anal. Biochem. 1984;137:380-388[Medline]
9.
Finch J. L., Brown A. J., Slatopolsky E. Differential effects of 1,25-dihydroxy-vitamin D3 and 19-nor-1,25-dihydroxy-vitamin D2 on calcium and phosphorus resorption in bone. J. Am. Soc. Nephrol. 1999;10:980-985
10.
Fox J. Hypocalcemia, but not PTH or hypophosphatemia, induces a rapid increase in 1,25(OH)2D3 levels in rats. Am. J. Physiol. 1992;262:E211-E215
11. Francis R. M., Peacock M., Storer J. H., Davies A. E., Brown W. B., Nordin B. E. Calcium malabsorption in the elderly: the effect of treatment with oral 25-hydroxyvitamin D3. Eur. J. Clin. Invest. 1983;13:391-396[Medline]
12. Fraser D. R. The physiological economy of vitamin D. Lancet i 1983;:969-972
13. Garabedian M., Bainsel M., Mallet E., Guillozo H., Toppet M., Grimberg R., NGuen T. M., Balsan S. Circulating vitamin D metabolite concentrations in children with nutritional rickets. J. Pediatrics 1983;103:381-386[Medline]
14. Gensure R. C., Antrobus S. D., Fox J., Okwueze M., Talton S. Y., Walters M. R. Homologous up-regulation of vitamin D receptors is tissue specific in the rat. J. Bone Miner. Res. 1998;13:454-463[Medline]
15. Goff J. P., Horst R. L., Uskokovic M. 1,25,28-Trihydroxyvitamin D2 up-regulates renal vitamin D receptor without causing hypercalcemia. Blood Pressure 1993;3:1825-1828
16.
Goff J. P., Reinhardt T. A., Beckman M. J., Horst R. L. Contrasting effects of exogenous 1,25-dihydroxyvitamin D [1,25-(OH)2D] versus endogenous 1,25-(OH)2D, induced by dietary calcium restriction, on vitamin D receptors. Endocrinology 1990;126:1031-1035
17. Gray R. W. Control of plasma 1,25-(OH)2-vitamin D concentrations by calcium and phosphorus in the rat: effects of hypophysectomy. Calcif. Tissue Int. 1981;33:485-488[Medline]
18. Haddad J. G., Matsuoka L. Y., Hollis B. W., Hu Y. Z., Wortsman J. Human plasma transport of vitamin D after its endogenous synthesis. J. Clin. Invest. 1993;91:2552-2555
19. Heaney R. P. Calcium and vitamin D in human nutrition. Lipkin M. Newmark H. L. Kelloff G. J. eds. Calcium, Vitamin D, and Prevention of Colon Cancer 1991:9-10 CRC Press Boca Raton, Florida
20.
Heaney R. P., Barger-Lux M. J., Dowell M. S., Chen T. C., Holick M. F. Calcium absorptive effects of vitamin D and its major metabolites [In Process Citation]. J. Clin. Endocrinol. Metab. 1997;82:4111-4116
21. Hollis B. W., Kilbo T. The assay of circulating 1,25(OH)2D using non-ene-capped C18 silica: performance and validation. Norman A. W. Schaefer K. Grigoleit H.-G. vHerrath D. eds. Vitamin D: Molecular, Cellular and Clinical Endocrinology 1988:710-719 W deGruyter Berlin.
22. Hsu C. H., Patel S. 25-Hydroxyvitamin D metabolism and its effect on calcitriol metabolism in experimental renal failure. J. Lab. Clin. Med. 1990;116:51-57[Medline]
23.
Hughes M. R., Brumbaugh P. F., Hussler M. R., Wergedal J. E., Baylink D. J. Regulation of serum 1alpha,25-dihydroxyvitamin D3 by calcium and phosphate in the rat. Science 1975;190:578-580
24. Jerome C. P., Colwell A., Eastell R., Russell R. G., Trechsel U. The effect of rat parathyroid hormone (1–34) infusion on urinary 3-hydroxypyridinium cross-link excretion in the rat. Bone Miner 1992;19:117-125[Medline]
25. Koshizuka K., Kubota T., Said J., Koike M., Binderup L., Uskokovic M., Koeffler H. P. Combination therapy of a vitamin D3 analog and all-trans-retinoic acid: effect on human breast cancer in nude mice. Anticancer Res 1999;19:519-524[Medline]
26.
Liel Y., Shany S., Smirnoff P., Schwartz B. Estrogen increases 1,25-dihydroxyvitamin D receptors expression and bioresponse in the rat duodenal mucosa. Endocrinology 1999;140:280-285
27. McKenna M. J., Freaney R. Defining hypovitaminosis D in the elderly. Burckhardt P. Dawson-Hughes B. Heaney R. P. eds. Nutritional Aspects of Osteoporosis 1998:268-277 Springer-VerlagAME> New York
28. Meyer A. S., Schmidt T. J. Differential effects of agonist and antagonists on autoregulation of glucocorticoid receptors in a rat colonic adenocarcinoma cell line. J. Steroid Biochem. Mol. Biol. 1997;62:97-105[Medline]
29. Pratt D. A., Daniloff Y., Duncan A., Robins S. P. Automated analysis of the Pyridinium crosslinks of collagen in tissue and urine using solid-phase extraction and reversed-phase high-performance liquid chromatography. Analyt. Biochem. 1992;207:168-175
30. Rasmussen H., Baron R., Broadus A., DeFronzo R., Lang R., Horst R. 1,25(OH)2D3 is not the only D metabolite involved in the pathogenesis of. Am. J. Med. 1980;69:360-368[Medline]
31. Reasner C. A. Vitamin D metabolism in Mexican-Americans. J. Bone & Min. Res. 1990;5:793-794
32. Reasner C. A., Dunn J. F., Fetchick D. A., Liel Y., Hollis B. W., Epstein S.S.J., Mundy G. R., Bell N. H., Dunn J. F., Fetchick D. A., Liel Y., Hollis B. W., Epstein S.S.J., Mundy G. R., Bell N. H. Alteration of vitamin D metabolism in Mexican-Americans [see comments]. J. Bone & Min. Res. 1990;5:13-17[Medline]
33. Reeves P. G., Nielsen F. H., Fahey G.C.J. AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J. Nutr. 1993;123:1939-1951
34. Sambrook J., Fritsch E. F., Maniatis T. Molecular Cloning, A Laboratory Manual 1989 Cold Spring Harbor Laboratory Press Cold Spring Harbor, N.Y.
35.
Sandgren M. E., DeLuca H. F. Serum calcium and vitamin D regulate 1,25-dihydroxyvitamin D3 receptor concentration in rat kidney in vivo. Proc. Natl. Acad. Sci. USA 1990;87:4312-4314
36. Solvsten H., Svendsen M. L., Fogh K., Kragballe K. Upregulation of vitamin D receptor levels by 1,25(OH)2 vitamin D3 in cultured human keratinocytes. Arch. Dermatol. Res. 1997;289:367-372[Medline]
37. Vieth R. The mechanisms of vitamin D toxicity. Bone & Min 1990;11:267-272
38.
Vieth R. Simple method for determining specific binding capacity of vitamin D-binding protein and its use to calculate the concentration of "free" 1,25-dihydroxyvitamin D. Clin. Chem. 1994;40:435-441
39. Vieth R., Chan A., Pollard A. 125I-RIA kit cannot distinguish vitamin D deficiency as well as a more specific assay for 25-hydroxyvitamin D. Clin. Biochem. 1995;28:175-179[Medline]
40.
Vieth R., Fraser D. Kinetic behavior of 25-hydroxyvitamin D-1-hydroxylase and -24- hydroxylase in rat kidney mitochondria. J. Biol. Chem. 1979;254:12455-12460
41. Vieth R., Fraser D., Kooh S. W. Low dietary calcium reduces 25-hydroxycholecalciferol in plasma of rats. J. Nutr. 1987;117:914-918
42. Vieth R., Milojevic S. Moderate vitamin D3 supplementation lowers serum 1,25-dihydroxy-vitamin D3 in rats. Nutr. Res. 1995;15:725-731
43. Yao J., Kathpalia P., Bushinsky D. A., Favus M. J. Hyperresponsiveness of vitamin D receptor gene expression to 1,25- dihydroxyvitamin D3. A new characteristic of genetic hypercalciuric stone-forming rats. J. Clin. Invest. 1998;101:2223-2232[Medline]
This article has been cited by other articles:
|
|
 |
|
  J. C. Fleet, C. Gliniak, Z. Zhang, Y. Xue, K. B. Smith, R. McCreedy, and S. A. Adedokun Serum Metabolite Profiles and Target Tissue Gene Expression Define the Effect of Cholecalciferol Intake on Calcium Metabolism in Rats and Mice J. Nutr., June 1, 2008; 138(6): 1114 - 1120. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. McCann and B. N. Ames Is there convincing biological or behavioral evidence linking vitamin D deficiency to brain dysfunction? FASEB J, April 1, 2008; 22(4): 982 - 1001. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Leach Jr. and E. Monsonego-Ornan Tibial Dyschondroplasia 40 Years Later Poult. Sci., October 1, 2007; 86(10): 2053 - 2058. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M Kimball, M. R Ursell, P. O'Connor, and R. Vieth Safety of vitamin D3 in adults with multiple sclerosis Am. J. Clinical Nutrition, September 1, 2007; 86(3): 645 - 651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Tryfonidou, M. A. Oosterlaken-Dijksterhuis, J. A. Mol, T. S. G. A. M. van den Ingh, W. E. van den Brom, and H. A. W. Hazewinkel 24-Hydroxylase: potential key regulator in hypervitaminosis D3 in growing dogs Am J Physiol Endocrinol Metab, March 1, 2003; 284(3): E505 - E513. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Vieth, Y. Ladak, and P. G. Walfish Age-Related Changes in the 25-Hydroxyvitamin D Versus Parathyroid Hormone Relationship Suggest a Different Reason Why Older Adults Require More Vitamin D J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 185 - 191. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Vieth Vitamin D ingestion and changes to rat aorta Cardiovasc Res, November 1, 2002; 56(2): 323 - 324. [Full Text] [PDF]
|
|
|
|
|
|
M. A. Tryfonidou, J. J. Stevenhagen, G.J.C.M. van den Bemd, M. A. Oosterlaken-Dijksterhuis, H. F. DeLuca, J. A. Mol, W. E. van den Brom, J.P.T.M. van Leeuwen, and H.A.W. Hazewinkel Moderate Cholecalciferol Supplementation Depresses Intestinal Calcium Absorption in Growing Dogs J. Nutr., September 1, 2002; 132(9): 2644 - 2650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Vieth Reply to FAJ Muskiet et al Am. J. Clinical Nutrition, December 1, 2001; 74(6): 863 - 864. [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
