Departments of 1 Clinical Sciences of Companion Animals and 2 Pathology, Faculty of Veterinary Medicine, Utrecht University, 3508 TD Utrecht, The Netherlands
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ABSTRACT |
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A group of growing
dogs supplemented with cholecalciferol (vitamin D3; HVitD)
was studied vs. a control group (CVitD; 54,000 vs. 470 IU vitamin
D3/kg diet, respectively) from 3 to 21 wk of age. There
were no differences in plasma levels of Pi and
growth-regulating hormones between groups and no signs of vitamin
D3 intoxication in HVitD. For the duration of the study in
HVitD vs. CVitD, plasma 25-hydroxycholecalciferol levels increased 30- to 75-fold; plasma 24,25-dihydroxycholecalciferol levels increased 12- to 16-fold and were accompanied by increased renal 24-hydroxylase gene
expression, indicating increased renal 24-hydroxylase activity.
Although the synthesis of 1,25-dihydroxycholecalciferol
[1,25(OH)2D3] was increased in HVitD vs.
CVitD (demonstrated by
[3H]1,25(OH)2D3 and increased
renal 1-hydroxylase gene expression), plasma
1,25(OH)2D3 levels decreased by 40% as a
result of the even more increased metabolic clearance of
1,25(OH)2D3 (demonstrated by
[3H]1,25(OH)2D3 and increased
gene expression of intestinal and renal 24-hydroxylase). A shift of the
Ca set point for parathyroid hormone to the left indicated increased
sensitivity of the chief cells. Effective counterbalance was provided
by hypoparathyroidism, hypercalcitoninism, and the key regulator
24-hydroxylase, preventing the development of vitamin D3 toxicosis.
25-hydroxycholecalciferol; 1,25-dihydroxycholecalciferol; 24,25-dihydroxycholecalciferol; calcitonin; parathyroid hormone
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INTRODUCTION |
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IT IS WELL ESTABLISHED
THAT the diet and the skin are sources of cholecalciferol
(vitamin D3; see Ref. 27). Vitamin
D3 is converted in the liver to 25-hydroxycholecalciferol
[25(OH)D3] and with a sequential hydroxylation primarily
in the kidney to 1,25-dihydroxycholecalciferol
[1,25(OH)2D3] with aid of 1-hydroxylase and to 24,25-dihydroxycholecalciferol
[24,25(OH)2D3] with the aid of
24-hydroxylase. 1,25(OH)2D3 is the most
biologically active vitamin D3 metabolite with regard to Ca
metabolism and skeletal growth with a variety of target organs,
including the skeleton, intestine, and kidney (7).
24,25(OH)2D3 is a biologically active metabolite mainly directed to the skeleton (6, 56) but
also with putative actions at the intestine (39, 40, 59,
60).
The rate of renal synthesis of 1,25(OH)2D3 is
directly responsive to plasma levels of Pi, growth hormone
(GH), insulin-like growth factor I (IGF-I), parathyroid hormone (PTH),
and calcitonin (CT; see Refs. 24, 36, and
41). Regulatory feedback on 1-hydroxylase is provided
by 1,25(OH)2D3 by induction of 24-hydroxylase
activity and thus conversion of 1,25(OH)2D3
into less biologically active metabolites in its target tissues,
including intestine, kidney, and bone (7, 52). In the
kidney, 24-hydroxylase activity is enhanced by
1,25(OH)2D3 and downregulated by PTH (48,
62, 63), whereas in the intestine, 24-hydroxylase is enhanced by 1,25(OH)2D3 and downregulated by CT
(3).
The period of rapid growth is a formidable challenge for vitamin
D3 metabolism in preserving skeletal mineralization. There are few investigations in young intact animals that have studied the
hormonal regulation of excessive vitamin D3 with respect to the activity of 1-hydroxylase and 24-hydroxylase (4, 47, 57,
58). However, these studies confined their measurements to
single-moment observations, possibly because of technical limitations. Therefore, there is insufficient knowledge concerning the
time-dependent changes of vitamin D3 metabolism during
elevated dietary vitamin D3 intake. Obtaining insight into
the complexity of vitamin D3 homeostasis in relation to its
regulating hormones and enzymes requires large research animals for
long-term studies on the effect of dietary vitamin D3
supplementation. Dogs are of adequate size to allow for simultaneous
and sequential sampling of blood and tissue material during the rapid
growth period. Additional advantages are complete dependence on the
dietary intake of vitamin D3 (29) and thus
easy regulation of the vitamin D3 status without
interpretation problems caused by seasonal variation of plasma vitamin
D3 metabolite concentrations.
To study the time-dependent changes and interactions of hormones
implicated in Ca homeostasis during long-term dietary vitamin D3 supplementation and their effect on in vivo regulation
of 1-hydroxylase and 24-hydroxylase, a control group of dogs was
investigated vs. an ample 100-fold vitamin D3-supplemented
group for 18 wk immediately after partial weaning. Calciotropic and
growth-regulating hormones were measured throughout the study. The
influence of long-term vitamin D3 supplementation on
parathyroid chief cell and thyroid C cell function was evaluated by
dynamic tests. Furthermore, the gene expression of renal
1
-hydroxylase and 24-hydroxylase, and intestinal 24-hydroxylase, was
determined, and the production and clearance rates of
1,25(OH)2D3 were investigated.
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MATERIALS AND METHODS |
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Animals and diets. The Utrecht University Ethical Committee for Animal Care and Use approved all procedures. Sixteen Great Danes, originating from three different litters, were divided into the following two groups at 3 wk of age: a control group (n = 9, CVitD) and a dietary vitamin D3-supplemented group (n = 7, HVitD). Pups were raised on an extruded diet formulated to be comparable in energy, Ca, and phosphate content (450 kcal, 9.5 g, and 7.5 g/100 g dry matter diet, respectively). The control diet was formulated to contain the recommended amount of 500 IU vitamin D3/kg diet (1, 38), whereas the supplemented vitamin D3 diet was formulated to contain a total of 50,000 IU vitamin D3/kg diet. Diets were analyzed for their vitamin D3 content (55) by a reference laboratory (TNO Nutrition and Food Research, Zeist, The Netherlands), and the analyzed vitamin D3 content was 470 and 54,000 IU vitamin D3/kg diet for the CVitD and HVitD, respectively, with no detectable traces of ergocalciferol. From 3 until 6 wk of age, pups received their diet as a gruel in addition to the bitch milk and received dry diet exclusively later on. Body weight was measured biweekly, and food was provided at two times maintenance energy requirements of each dog (31) for the duration of the study.
Blood measurements. At 7, 10, 13, 16, and 19 wk of age, blood samples were collected after an overnight fast. Blood samples for the measurement of plasma total Ca and Pi levels were transferred to heparin tubes, centrifuged, and measured according to standard procedures (Beckman Industries).
Blood samples for hormone analysis were immediately transferred to EDTA-coated tubes and placed on ice until centrifuged. Plasma was stored atDynamic tests on C cell and chief cell function. Tests were performed after overnight food deprivation with a week between tests to avoid reciprocal influences. Ca infusion tests were performed at 6, 12, and 18 wk of age, whereas EDTA infusion tests were performed at 7, 13, and 19 wk of age in all dogs.
In short, during the Ca stimulation tests, dogs were kept in a sitting position, and calcium gluconate (13.75 mg calcium gluconate/ml; Sandoz Pharma, Basel, Switzerland) was administered for 3-5 s through an indwelling catheter in the cephalic vein. The total dose was 0.28 ml calcium gluconate/kg body wt, equivalent to a dose of 2.52 mg Ca2+/kg body wt. Blood samples were taken by jugular venipuncture at1-Hydroxylase and 24-hydroxylase gene expression.
Gene expression of 1
-hydroxylase and 24-hydroxylase was determined
at the middle and the end of the study in all dogs. At 10 wk of age,
five duodenal forceps biopsies were taken under endoscopic guidance
with the dog under general anesthesia. In addition, at 11 wk of age,
two kidney biopsies were obtained with the aid of fine needle biopsy
under guidance of echography with the dog under general anesthesia. At
the end of the study, i.e., at 21 wk of age, the animals were killed
with an overdose of pentobarbital sodium, and biopsies from the kidney
and mucosa of the proximal duodenum were sampled. Kidney and intestinal
biopsies were frozen immediately in liquid nitrogen and stored at
70°C until required for RNA isolation.
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Endogenous metabolic clearance rate and production rate of
1,25(OH)2D3.
At 19 wk of age, the metabolic clearance rate (MCR) of
1,25(OH)2D3 was determined in eight CVitD and
seven HVitD dogs with the aid of a bolus injection with
1,25-dihydroxy[23,24(n)-3H]cholecalciferol
{[3H]1,25(OH)2D3, sp act
10.5 GBq/mg; Amersham Pharmacia Biotech, UK} by techniques described
previously (19, 23). In short, after an intravenous
administration of ~3.7 KBq
[3H]1,25(OH)2D3, blood samples
were drawn at 4, 6, 8, 10, 15, 20, 30, 45, 60, and 90 min and at 2, 3, 4, 5, 6, 10, 12, and 24 h after the injection; transferred
immediately to EDTA-coated tubes; and placed on melting ice until
centrifuged and processed further. The plasma disappearance curve of
[3H]1,25(OH)2D3 was obtained by
counting plasma samples (0.5 ml) with 4 ml scintillation fluid (Ultima
Gold; Packard Bioscience, Groningen, The Netherlands) in a liquid
scintillation counter (1212 Rackbeta; LKB Wallac, Turku, Finland) for
30 min/sample. By means of a computerized nonlinear least-squares
fitting procedure, a biexponential function
C(t) = Ae
at + Be
bt was fitted to the plasma
[3H]1,25(OH)2D3 concentrations.
The MCR of 1,25(OH)2D3 was calculated by the
quotient of the injected dose (D) of
[3H]1,25(OH)2D3 and the integral
of plasma specific activity of [3H]1,25(OH)2D3 as follows:
MCR = D
1 · day
1) was
derived from the formula PR = MCR × endogenous circulating 1,25(OH)2D3, where the endogenous circulating
1,25(OH)2D3 is the plasma
1,25(OH)2D3 level at 19 wk of age.
Statistical analysis. Statistical analyses were performed using SPSS for Windows 10.1 (SPSS). Homogeneity of variance was tested according to Levene. Differences between groups were analyzed by the two-sided Student's t-test. The AUC of the basal plasma PTH and CT levels were calculated for the duration of the study for both groups. Values were considered to be significant at P < 0.05. Results are presented as means ± SE. For the analysis of the pre- and postinfusion plasma levels within the group, baseline values were compared with the corresponding maximal response values by a one-sided Student's t-test for paired data. Differences in RL0, RLBaseline, and CaSfor PTH between groups were analyzed by the two-sided Student's t-test.
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RESULTS |
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Dogs had good general health, grew well, and consumed the total amount of food that was offered daily. Consequently, energy and food intake per kilogram metabolic body weight (kg0.75) did not differ between groups. HVitD consumed ~135 times more vitamin D3/kg body wt compared with CVitD. The mean growth rate per week for the entire study period was 1.5 ± 0.4 and 1.6 ± 0.3 kg body wt/wk of age for CVitD and HVitD, respectively, and was not significantly different between groups.
Blood measurements.
Plasma Ca levels did not differ between groups for the duration of the
study (Fig. 1). Plasma Pi
levels did not differ between groups and ranged from 2.68 ± 0.03 to 2.95 ± 0.03 mmol/l for the duration of the study. Plasma
levels of 25(OH)D3 were 30- to 70-fold increased, and
levels of 24,25(OH)2D3 were 12- to 16-fold
increased in HVitD vs. CVitD for the duration of the study (Fig. 1).
Plasma 1,25(OH)2D3 levels did not differ
between groups at 7 wk of age, whereas for the remainder of the study
they were decreased significantly in HVitD vs. CVitD (Fig. 1). Most
basal plasma PTH levels and the PTH AUC were significantly lower in
HVitD vs. CVitD for the duration of the study (Fig. 1). Basal plasma CT
levels were highly variable, being mainly increased in the beginning
period of the study in HVitD vs. CVitD (Fig. 1). The CT AUC for the
duration of the study was increased significantly in HVitD vs. CVitD.
Plasma GH and IGF-I levels did not differ between groups and increased and decreased with age from 19.7 ± 2.4 to 6.6 ± 1.1 µg/l
and from 216 ± 24 to 360 ± 27 µg/l, respectively.
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Ca and EDTA infusion tests.
Plasma Ca
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Gene expression levels of 1-hydroxylase and 24-hydroxylase.
At all ages, gene expression levels of renal 1
-hydroxylase,
24-hydroxylase, and intestinal 24-hydroxylase were increased significantly in HVitD vs. CVitD, respectively (Fig.
3). There were no age-dependent
differences within each group.
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MCR and PR of 1,25(OH)2D3.
At 19 wk of age, MCR and PR of 1,25(OH)2D3
were significantly higher in HVitD vs. CVitD (Fig.
4).
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DISCUSSION |
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Dietary 135-fold vitamin D3 supplementation during growth had striking influences on the main vitamin D3 metabolites in plasma and was accompanied by hypoparathyroidism, lowered CaSfor PTH, and hypercalcitoninemia. Plasma Pi, GH, and IGF-I levels could be excluded as differentially regulating factors, since they did not differ between groups, leaving Ca2+, PTH, CT, vitamin D3 intake, and vitamin D3 metabolites as the main regulating factors in vitamin D3 metabolism for the total duration of the study.
Effects of hypervitaminosis D3 on the main vitamin
D3 metabolites.
At states of excessive vitamin D3 as in HVitD, the abundant
substrate is metabolized by the loosely regulated 25-hydroxylase (53), and plasma 25(OH)D3 levels increase
(47). In HVitD, the 12- to 16-fold increased plasma
24,25(OH)2D3 levels were attributed to the
increased renal 24-hydroxylase activity indicated by the striking 10.5- and 6-fold increase of the renal 24-hydroxylase gene expression levels
at both measure points compared with CVitD. Plasma 25(OH)D3
and 24,25(OH)2D3 levels may rise far above the binding capacity of the vitamin D-binding protein (DBP) and displace 1,25(OH)2D3 from DBP, resulting in an increase
of the free plasma 1,25(OH)2D3 levels
(43). The latter may have resulted in increased biological
activity of 1,25(OH)2D3 without a concomitant
increase in the total plasma 1,25(OH)2D3
levels. The lowered total plasma 1,25(OH)2D3
levels in HVitD were mainly a consequence of increased MCR of
1,25(OH)2D3 in HVitD vs. CVitD with conversion
of 1,25(OH)2D3 into less biologically active
products (33), including 1,24,25-trihydroxycholecalciferol (14). In support, the significantly increased renal and
intestinal 24-hydroxylase gene expression indicated upregulation of the
24-oxidation pathway. At the same time, in HVitD, the PR of
1,25(OH)2D3 was increased significantly, being
in accordance with the 9.3- and 8-fold increases in the renal
1-hydroxylase gene expression at both measure points compared with
CVitD. Renal synthesis of 1,25(OH)2D3 is
regulated tightly by Ca, 1,25(OH)2D3, PTH, and
CT (7, 35, 36). Increased plasma Ca2+ levels
at the end of the study did not seem to affect the production of
1,25(OH)2D3 in HVitD, whereas the decreased
plasma 1,25(OH)2D3 levels indicated withdrawal
of homologous negative feedback on the production of
1,25(OH)2D3. Plasma PTH levels were decreased significantly for the duration of the study in HVitD and thus can be
excluded as a relevant upregulating factor of the production of
1,25(OH)2D3 (49). Plasma CT levels
were, however, at high levels in HVitD, being a potential upregulator
of the production of 1,25(OH)2D3
(49). In accordance, Beckman et al. (4) hold increasing plasma CT levels during hypercalcemia responsible for stimulating the production of 1,25(OH)2D3. It
seems conceivable to suggest that the stimulatory effect of CT on
1,25(OH)2D3 production is an additional
defensive mechanism in growing animals to maintain positive Ca balance
required for optimal skeletal mineralization.
24-Hydroxylase is a potent key regulator. In hypervitaminosis, D3 24-hydroxylase seems to play a counterregulating key role (3, 4). 24-Hydroxylase has been reported to be upregulated by 1,25(OH)2D3 at the transcriptional level (61) and downregulated by PTH (62, 63), more so at the kidney level than at the intestinal level (48) and by CT at the intestinal level (3). Relevant upregulators of 24-hydroxylase may have been the increased free plasma 1,25(OH)2D3 levels, as well as 25(OH)D3, which has been reported to act directly on target organs of 1,25(OH)2D3 both at supraphysiological (12) and physiological concentrations (16, 26). Hypoparathyroidism in HVitD and thus reduction of the downregulatory effect of PTH on kidney 24-hydroxylase assured an active 24-hydroxylase pathway for the regulation of the circulating 25(OH)D3 and 1,25(OH)2D3. Hypercalcitoninism resulted accordingly in HVitD in an increment of 24-hydroxylase gene expression of a smaller magnitude on an intestinal than on a renal level. In summary, the increased renal synthesis of 1,25(OH)2D3 was provided with an effective means of its deactivation by upregulation of the 24-oxidation pathway in target organs (intestine and kidney), and consequently plasma 1,25(OH)2D3 levels were lower in HVitD than in CVitD, as has been reported to occur in rats by Beckman et al. (4).
Effects of hypervitaminosis D3 on PTH secretion and production. Although basal plasma PTH levels and RL0 of PTH induced by an elevation or decrease of Ca2+ were lower in HVitD vs. CVitD, the RLBaseline of PTH induced by elevation of Ca2+ did not differ between groups. This indicated that, in HVitD, regardless of the lower basal PTH secretion levels, the chief cells retained their responsiveness to an elevation or decrease of Ca2+. Exceptionally, at the end of the study, RLBaseline of PTH induced by a decrease of Ca2+ was significantly lower in HVitD vs. CVitD, indicating a decrease in the maximal secretion rate of PTH and a probable initiation of hypoparathyroidism. The decreased PTH secretion rate resulting in decreased basal plasma PTH levels may be attributed either to increased sensitivity of the parathyroid gland to any given plasma Ca2+ level, to a decrease in PTH production, to an adjustment of the degradation of the newly synthesized PTH at the chief cell level, or any combination. This consideration is rather tentative, since PTH gene expression levels and the secretory profile of the parathyroid gland are not available (i.e., intact PTH in relation to carbon-terminal PTH fragments). Increased sensitivity of the parathyroid gland in the beginning and middle of the study is indicated by the significantly lower CaSfor PTH in HVitD vs. CVitD. The shift of the CaSfor PTH to the left can be attributed to induction of the chief cell Ca-sensing receptor (CaR; see Ref. 11). Accordingly, 1,25(OH)2D3 administration has been reported to result in a shift of the CaSfor PTH to the left (17, 18, 32) and in increased CaR gene expression of the parathyroid gland in vitamin D-deplete and -replete rats (8, 13). At a lower CaSfor PTH, the production of PTH is not necessarily decreased, although increased free plasma 1,25(OH)2D3, the abundantly circulating 25(OH)D3, and increased plasma Ca2+ levels have been reported to have an inhibiting effect on the production of PTH (50, 51). Histological evaluation of the activity of the parathyroid glands at the end of the study did not show any obvious differences between HVitD and CVitD dogs. A modified demand for intact biologically active PTH may also have been achieved by adjustment of the parathyroid secretion profile toward an increased secretion of carbon-terminal fragments of PTH, as reported in hypercalcemic states or treatment with 1,25(OH)2D3 (15) without necessarily a decrease in production of PTH.
Effects of hypervitaminosis D3 on CT secretion. The principal regulator of CT secretion is the increase in plasma Ca2+ levels (2). Only in the beginning and middle of the study were the increased CT secretion and increased responsiveness of C cells to stimuli indicated by the significantly higher RL0 and RLBaseline of CT in HVitD vs. CVitD during stimulation or depression of CT secretion. These findings were independent of the basal plasma Ca2+ levels and indicated increased CT production with or without C cell hyperplasia (22, 30, 42). However, C cell hyperresponsiveness seemed to be elapsing with the duration of the study, since the differences in CT secretion and responsiveness between groups were diminished at the end of the study. The latter was also verified by histological evaluation at the same time point. Responsiveness of the C cells to changes of the plasma Ca2+ levels and the production of CT may be mediated by the extracellular CaR of C cells (11, 21). It remains to be elucidated which positive regulator or mediator may have resulted in increased secretion of CT and responsiveness of the C cells in HVitD, including endocrine systems directly or indirectly connected to bone metabolism (45). The biological significance of an increase in CT during states of positive Ca balance, as during growth, is mainly directed at avoiding hypercalcemia by decreasing osteoclastic resorption and enhancing deposition of Ca in bone (46).
Conclusively, during 135-fold vitamin D3 supplementation in growing dogs despite the increase in 1,25(OH)2D3 production, plasma 1,25(OH)2D3 levels were decreased as a result of an apparently even greater catabolism of 1,25(OH)2D3 by 24-hydroxylase. Downregulation of the PTH secretion and hypercalcitoninism provided extra protection against hypercalcemia by cessation of bone resorption and thus reduction of the liberation of Ca. There was only a slight increase in plasma Ca2+ levels at the end of the study, suggesting that the total burden of vitamin D3 might have reached a critical stage. However, there was no clear shift toward a vitamin D3 toxic state with the typical clinical signs of impaired growth, hypercalcemia and hyperphosphatemia, and kidney failure. In spite of the 135-fold vitamin D3 supplementation, HVitD dogs grew well and retained normophosphatemia and normal plasma total Ca levels for most of the study. Efficient hormonal counteraction with a key role for 24-hydroxylase prevented the development of vitamin D3 toxicosis during the course of the study. ![]() |
ACKNOWLEDGEMENTS |
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Stable metabolites of 25(OH)D3 and 24,25(OH)2D3 were kindly provided by Dr. J. P. van de Velden (Solvay Pharmaceuticals, Weesp, The Netherlands). We acknowledge the clinic attendants for good care of the pups and their assistance in performing the experiments, and the assistance of the Biochemical Laboratory and the Department of Anaesthesiology. Drs. E. den Hertog, M. Diaz, A. van Dongen, and G. Voorhout are acknowledged for assistance in sampling the intestinal and kidney biopsies. We thank Dr. J. E. van Dijk for excellent assistance in histological evaluation.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. A. Tryfonidou, Dept. of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht Univ., Yalelaan 8, 3584 CM Utrecht, The Netherlands (E-mail: M.A.Tryfonidou{at}vet.uu.nl).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published November 19, 2002;10.1152/ajpendo.00236.2002
Received 6 May 2002; accepted in final form 24 October 2002.
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