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Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706 From the National Institutes of Health and a fund from the Wisconsin Alumni Research Foundation.
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • vitamin A • vitamin D • bone mineralization • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Early on, the
ability to cure the bone mineralization disorder rickets was believed
to be a property of vitamin A since this activity also was found in cod
liver oil (Mellanby 1919
). However, it was shown that
the ability to cure rickets is a function of vitamin D rather than A
found in cod liver oil (McCollum et al. 1922
). Later
research revealed that vitamin A (retinol) has many functions: it is
required for the visual cycle, is needed for growth and development and
is required for male and female reproduction (Sporn and Roberts 1984
). Vitamin D, on the other hand, is required for
maintenance of calcium and phosphorus homeostasis, mineralization and
maintenance of bone as well as other less well-defined actions
(Jones et al. 1998
). Both vitamins must be converted to
specific metabolites for function.
Vitamin D is metabolized to a single hormonal form,
1,25-dihydroxycholecalciferol
[1,25-(OH)2D3]3
that carries out all its known functions. This hormone acts through a
nuclear receptor to regulate specific gene transcription. Vitamin A or
retinol is metabolized to retinaldehyde for the visual function
(Saari 1994
). Retinaldehyde is further metabolized to
all-trans-retinoic acid and its 9-cis-isomer for
its function in growth, differentiation and embryonic development
(Hofman and Eichele 1994
). How retinol functions in
reproduction is largely unknown (Takahashi et al. 1975
,
Thompson et al. 1964
, Wellik and DeLuca 1995
, White et al. 1998
).
All-trans-retinoic acid acts through a series of receptors,
termed retinoic acid receptors (RAR) 
, ß and 
(Benbrook et al. 1988
, Brand et al. 1988
, Giguere et al. 1987
, Krust et al. 1989
, Petkovich et al. 1987
). Further, another series of retinoid receptors,
termed retinoid X receptors (RXR) that bind 9-cis-retinoic
acid, were found (Mangelsdorf et al. 1990
, and
1992
, Yu et al. 1991
). All the retinoid
receptors are members of a superfamily of steroid-thyroid hormone
receptors (Evans 1988
, Green and Chambon 1988
). Also included in this family are the
1,25-(OH)2D3 receptor, the
peroxisome proliferator-activated receptor and the thyroid hormone
receptor (DiRenzo et al. 1997
). The RAR protein binds to
its response element in target genes as a heterodimer with RXR proteins
(Kliewer et al. 1992
, Yu et al. 1991
,
Zhang et al. 1992a
). The partner for the
1,25-(OH)2D3 receptor also
is an RXR protein (MacDonald et al. 1993
, Munder et al. 1995
). Hence, at least one basic link between the
vitamin A and vitamin D responsive systems is the common use of RXR for
heterodimer formation in transcriptive activity. Early work provided
evidence that vitamin A may antagonize the actions of vitamin D
(Grant and O’Hara 1957
, Weits 1952
and
1959
). We now report that vitamin A clearly antagonizes
the actions of vitamin D.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In all experiments, 21-d-old male, weanling rats (50–60 g) of the Holtzman strain (Harlan Sprague-Dawley, Indianapolis, IN) were used. They were maintained in individual overhanging wire cages and were allowed to consume distilled water and purified diet ab libitum. All experimental protocols were reviewed and approved by the Research Animal Resources Center (University of Wisconsin-Madison, Madison, WI).
The first experiment was designed to determine whether increasing
levels of retinyl acetate influence the mineralization activity of
small amounts of ergocalciferol in rats fed a rachitogenic diet. Rats
were fed a 1.2% calcium, 0.1% phosphorus diet, Diet 24 (DeLuca et al. 1961
), that produces severe rickets in 3 wk. This diet
was modified such that the fat-soluble supplement contained 5 g/L
-tocopherol (vitamin E; Sigma, St. Louis, MO) and 0.6 g/L
menadione (vitamin K; Sigma) but was devoid of vitamins A and D. The
indicated levels of vitamin A in the form of retinyl acetate (Sigma)
and ergocalciferol (vitamin D2; Sigma) were achieved by
providing additional supplements. In each case, the indicated amount of
vitamin D2 was dissolved in cottonseed-soybean oil
(Wesson oil, Hunt-Wesson Foods, Fullerton, CA) and given as an oral
supplement of 0.1 mL every 3 d. On each of two alternate days, the
rats were given vitamins E and K or the indicated amount of retinyl
acetate in 0.1 mL of Wesson oil. Control animals receiving no retinyl
acetate were given 0.1 mL of Wesson oil alone. The rats, therefore,
received a total of 0.1 mL of Wesson oil each day.
At the beginning of the experiment, one group (n = 6) was killed to determine initial femur ash content. The remaining rats were divided into five groups (n = 6). The administration of vitamin supplements was performed as described above with all rats fed 15.5 ng of vitamin D2 per day and one of the following levels of retinyl acetate: 0, 11.4, 345, 3448 or 8621 µg. This regimen was continued for 21 d. At this time, the rats were anesthetized and killed by decapitation. Blood was collected for serum calcium and phosphorus analyses. The right femur was removed from each rat and used for bone ash determination.
The second experiment was designed to determine what level of vitamin D2 could overcome this antagonistic action of high amounts of retinyl acetate. The experiment was carried out exactly as described above except that five additional levels of vitamin D2 were tested: 0, 5.2, 26, 129, 258 and 645 ng/d. The levels of retinyl acetate utilized were the same as previously described except the 345 µg/d dose was eliminated. Furthermore, in addition to blood and a femur, the radius and ulna were removed for measurement of metaphyseal width.
The third experiment tested whether retinyl acetate could antagonize
the ability of vitamin D2 to maintain serum calcium levels
in rats fed a normocalcemic diet. Rats were divided into four groups
(n = 6) and fed a 0.47% of calcium, 0.3% of
phosphorus diet, Diet 11 (Suda et al. 1970
). The
vitamins were administered as described for the first experiment with
retinyl acetate, vitamin D2 and vitamins E and K being
given on three alternate days. Two levels of vitamin D2 (0
and 5.2 ng/d) and three levels of retinyl acetate were given (0, 11.4
and 3448 µg/d). The experiment was carried out for 33 d. At this
time, rats were anesthetized and killed by decapitation. Only blood was
collected from these rats for serum calcium and phosphorus analyses.
Bone ash determination.
The femurs were cleaned of adhering tissue, wrapped individually in filter paper and extracted with 95% ethanol for 24 h using a Soxhlet extractor. This was followed by a 24-h extraction with diethyl ether, again using the Soxhlet extractor. The bones were dried for 12 h at 43°C and weighed. They were then ashed at 649°C for 16 h followed by determination of ash weight. Using these values, the percent and total ash per femur were calculated.
Measurement of metaphyseal width.
The distal radius and ulnae were removed, cleaned of adhering tissue and sliced lengthwise with a razor blade. They were soaked for 24 h in distilled water and stained with 1% silver nitrate under white light. As soon as the calcified areas were darkened, the bones were washed and immediately used to measure metaphyseal width. This width is the distance between the calcified epiphysis and the calcified spongiosa of bone.
Serum calcium and phosphorus.
For determination of serum calcium and phosphorus, blood samples were
obtained and centrifuged to yield serum. Calcium was determined by the
method of Harrison and Harrison (1955)
while serum phosphorus levels
were determined by the method of Fiske and Subbarow (1925)
.
Statistical analysis.
All data were analyzed using the Student’s t-test. A P < 0.05 value was considered to be a significant difference.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Increasing the level of retinyl acetate and holding the level of
vitamin D2 constant caused a progressive decrease
in the total amount of ash in the femur. In fact, in rats given 8621
µg of retinyl acetate, total ash was significantly less than the
level found in the rats at the beginning of the experiment. A similar
significant decrease was seen in percent ash with all levels of retinyl
acetate, except for the rats given 8621 µg of retinyl acetate. The
failure of these rats to grow resulted in the same amount of ash being
distributed in a smaller femur. Therefore, no apparent difference was
observed in percent femur ash between rats administered 345 and 8621
µg of retinyl acetate per day, while a clear reduction of total ash
accumulated occurred. The apparent reduction of growth observed in the
rats dosed with 8621 µg of retinyl acetate per day may be an
indication of vitamin A toxicity in this group.
|
). When vitamin D2 was as high as 645 ng/d,
changing the vitamin A level from 0 µg to 8621 µg/d had no effect
on the total femur ash and little effect on the percent femur ash, but
did increase the epiphyseal plate width. At 258 ng vitamin
D2/d, progressively increasing the retinyl
acetate supplementation significantly reduced the total femur ash and
significantly increased the epiphyseal plate width. The results were
more dramatic as the amount of vitamin D2 was
diminished. Even in the absence of supplementary vitamin
D2, some decrease in total femur ash was observed
with progressively increasing retinyl acetate dosage.
|
). A decrease in serum phosphorus concentration with increasing retinyl
acetate levels was clearly observable in the absence of supplementary
vitamin D2. Except for this group, no consistent
change was observed in terms of the action of retinyl acetate on the
serum mineral concentrations.
|
). Serum calcium concentration, without vitamin D2
in the diet, was 1.37 mmol/L. In rats administered 5.2 ng vitamin
D2/d without retinyl acetate supplementation, the
serum calcium level was raised to 2.34 mmol/L, an approximately normal
value. By increasing the retinyl acetate levels to 3448 µg/d, the
serum calcium response to 5.2 ng of vitamin D2
was eliminated. Thus, an antagonism of vitamin D2
by high doses of retinyl acetate is clearly evident in the elevation of
serum calcium.
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|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). This hormone, in turn, acts through
its receptor to either initiate or suppress gene transcription
(Ross et al. 1994
). To carry out this function, the
vitamin D receptor requires a retinoid X receptor (RXR) to bind the
vitamin D responsive elements (VDRE) found in responsive genes
(Munder et al. 1995
, Ross et al. 1994
).
The RXR series of receptors bind 9-cis-retinoic acid and can
initiate transcription of RXR responsive genes in a
ligand-dependent fashion (Heyman et al. 1992
,
Levin et al. 1992
, Mangelsdorf et al. 1991
). The RXR proteins appear to function as homodimers in
this capacity (Zhang et al. 1992b
). On the other hand,
retinoic acid receptors, RAR , ß, , appear to function as
heterodimers by binding to the response elements together with RXR
proteins (Kliewer et al. 1992
, Yu et al. 1991
, Zhang et al. 1992a
). Therefore, at the
molecular level both vitamin A and D require RXR proteins to function
as a partner in heterodimer formation in preparation for transcriptive
action. If in animals given large doses of vitamin A,
9-cis-retinoic acid can dominate or utilize much of the
RXR proteins that are available, it follows that the action of vitamin
D might be compromised. On the basis of such a hypothesis, we began to
reexamine whether vitamins A and D can be antagonistic, independent of
each other, or can act in a synergistic manner. The present results
argue strongly that there is an antagonism between vitamins A and D at
the physiological level. When 5.2 ng vitamin D2/d was given
to rats on a rachitogenic diet, increasing doses of retinyl acetate
clearly interfered with the action of vitamin D2. This
antagonism by retinyl acetate continued in the presence of increasing
amounts of vitamin D2, up to a dose of 645 ng vitamin
D2/d. Furthermore, the effect of daily administration of
5.2 ng vitamin D2 on maintenance of serum calcium
concentration of rats fed a normal calcium and phosphorus diet was
eliminated by the administration of 3448 µg of retinyl acetate/d.
Thus, there is little doubt that at small levels of vitamin D, vitamin
A serves as an antagonist to vitamin D action.
For many years, it was claimed that carotenes are rachitogenic. Grant,
O’Hara and Weits provided clear evidence that rickets could be induced
by the administration of natural sources of carotene (Grant and O’Hara 1957
, Weits 1952
and
1959
). Our results show that in rats fed purified diets
and with defined amounts of vitamins A and D, this antagonism is
clearly evident. It is not clear, however, how the excess vitamin A
interferes with the action of vitamin D. Although it is intriguing to
consider that it might be at the molecular level, since both vitamins
use the RXR proteins as a heterodimeric partner, no evidence is
presented that can argue for that position. Vitamin A could interfere
with the absorption of vitamin D, transport of vitamin D, conversion of
vitamin D to its active form, or vitamin A could stimulate the
metabolic degradation of vitamin D.
Some comment should be made concerning the conclusions that can be drawn from percent bone ash versus total ash. Percent ash of bone always reflects the growth of bone as well as the rate of mineralization. Thus, an animal that is not growing but continues to accumulate ash in a normal way will have an elevated percent ash value. It might be attractive to conclude that better mineralization has occurred, when in fact, retarded growth of organic matrix was responsible. In considering the data presented, it is essential that this important feature is recognized.
Because bone development is clearly affected by vitamin A status, one
possible mechanism which could explain the data presented, is that
vitamin A has a direct effect on bone, causing demineralization or
resorption. This might be supported by the observations found in
vitamin D-deprived rats given increasing amounts of vitamin
A. However, from Table 4
, it is clear that the elevation of serum
calcium in response to vitamin D is also antagonized by vitamin A. The
elevation of serum calcium of these rats is related to intestinal
absorption of calcium and the mobilization of calcium from bone. If
vitamin A were increasing bone resorption, serum calcium elevation
should have occurred with increasing doses of vitamin A. Quite the
opposite was true, indicating that the action of vitamin D was being
antagonized. Further, it is indeed possible that small amounts of
vitamin D are still present in the rats during depletion and that this
small amount of vitamin D is what is being antagonized by vitamin A in
the vitamin D-deprived rats (Table 3)
.
Having established a clear antagonism, it now remains to be determined what is the nature of this antagonism at the molecular level and can this also account for the reduced toxicity of vitamin D caused by high levels of vitamin A and vice versa.
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FOOTNOTES |
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3 Abbreviations used:, 1,25-(OH)2D3, 1,25-dihydroxycholecalciferol;
RXR, retinoid X receptor; RAR, retinoic acid receptor; vitamin D2, ergocalciferol; VDRE, vitamin D responsive elements.
Manuscript received March 29, 1999. Initial review completed May 11, 1999. Revision accepted August 5, 1999.
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C. M. Rohde and H. DeLuca Bone Resorption Activity of All-trans Retinoic Acid Is Independent of Vitamin D in Rats J. Nutr., March 1, 2003; 133(3): 777 - 783. [Abstract] [Full Text] [PDF]
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