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Department of Safety Sciences, Pfizer Global Research and Development, Ann Arbor, MI 48105 and * Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706
2To whom correspondence should be addressed. E-mail: deluca{at}biochem.wisc.edu.
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ABSTRACT |
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,25-dihydroxycholecalciferol [1,25(OH)2D3], or 24,24-difluoro-1,25-dihydroxycholecalciferol [24-F2-1,25(OH)2D3] in combination with various amounts of retinyl acetate or all-trans retinoic acid (ATRA) in a series of studies. Rats administered 1720 or 3440 µg retinyl acetate once every 3 d for 33 d in combination with 25.8 ng ergocalciferol or 25 ng cholecalciferol every 3 d had lower serum calcium and greater serum phosphorus concentrations than rats fed 0 or 11.4 µg retinyl acetate every 3 d. In addition, rats fed 400 µg ATRA/d in combination with 25.8 ng ergocalciferol every 3 d, 25 ng cholecalciferol every 3 d, 2–5 ng 1,25(OH)2D3/d, or 0.5–1 ng 24-F2-1,25(OH)2D3/d had significantly lower serum calcium and higher serum phosphorus concentrations than rats not given ATRA in the diet. Therefore, both retinyl acetate and ATRA are able to antagonize the action of ergocalciferol and cholecalciferol in vivo. Additionally, ATRA antagonizes the in vivo action of 1,25(OH)2D3 and an analog, 24-F2-1,25(OH)2D3, that cannot be 24-hydroxylated. Together, these results suggest that retinol does not antagonize the action of calciferol by altering the metabolism of calciferol or 1,25(OH)2D3, but does so by another mechanism.
KEY WORDS: • calciferol • retinol • retinol-calciferol interaction
Interactions between retinol and calciferol have been observed for many years and in several different species. Early experiments using nonpurified diets indicated that retinol, in the form of carotene, from green roughage inhibits the ability of calciferol to cure rickets, a bone mineralization disorder (1–5). Later work demonstrated that giving excess amounts of both vitamins simultaneously could partially ameliorate the toxic effects of calciferol in rats and birds (6–10). Additionally, large amounts of retinol were shown to affect the ability of ergocalciferol to normalize bone mineral under rachitic conditions and maintain normal serum calcium concentrations in the presence of normal dietary calcium and phosphorus concentrations in rats (11). More recently, retinyl palmitate was shown to decrease the 1,25-dihydroxycholecalciferol [1,25(OH)2D3]3 -dependent increase in serum calcium in humans (12).
Although an antagonistic relation between retinol and calciferol has been firmly established, the exact nature of this interaction has yet to be determined. Several studies indicated that retinol may affect the metabolism of calciferol (13,14). Retinol may either decrease the production of the active form of calciferol, 1,25(OH)2D3, or it may increase the destruction of this compound. Another possible mechanism of interaction is that retinol may affect the production of the vitamin D receptor (VDR) (15,16). However, this effect is not clearly established and may depend on species and cell type. A third possible mechanism is suggested by the fact that both all-trans retinoic acid (ATRA) and 1,25(OH)2D3, the active forms of retinol and calciferol, require the retinoid X receptor (RXR) to carry out their effects on gene transcription (17–19). Both ATRA and 1,25(OH)2D3 accomplish their biological functions by binding to specific receptors, retinoic acid receptor (RAR) and VDR, respectively (20,21). These proteins form heterodimers with RXR before binding to specific response elements in the promoter region of ATRA- and 1,25(OH)2D3-regulated genes (22,23). Hence, ATRA or 9-cis retinoic acid (9CRA), the ligand for RXR, may have some effect on 1,25(OH)2D3-induced gene expression. In fact, an RXR-specific ligand, LG100268, was shown to stimulate a calciferol-regulated gene, cytochrome P450 (CYP)24 (24).
Therefore, although an antagonistic interaction between retinol and calciferol has been established in vivo, there is no clear explanation of how this antagonism occurs. The purpose of this study was to investigate the interaction between the 2 vitamins and to gain a better understanding of the mechanism behind it.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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-tocopherol (vitamin E), and menadione (vitamin K) were all purchased from Spectrum. Retinyl acetate, ergocalciferol, and cholecalciferol were all purchased from Sigma. 1,25(OH)2D3 was purchased from Tetrionics. 24,24-Difluoro-1,25-dihydroxycholecalciferol [24-F2-1,25(OH)2D3] was prepared as previously described (25). [26,27-3H]-1,25(OH)2D3 (163 Ci/mmol) was obtained from New England Nuclear. Animals and diets. In all experiments, male weanling (20 ± 1 d old, 50–60 g) Holtzman rats (Harlan Sprague Dawley) were used. They were maintained in individual overhanging wire cages with free access to distilled water. All rats were fed purified diets based on those described by Suda et al. (26). At the end of the experiments, rats were anesthetized and killed by decapitation. All experimental protocols were reviewed and approved by the Research Animal Resources Center (RARC, University of Wisconsin-Madison).
Retinol and calciferol depletion. Upon arrival, rats were placed in a room with incandescent lighting and fed the diet described by Suda et al. (26). Rats were weighed 2–3 times weekly to record growth as an indicator of retinol status. Before beginning experiments, rats were tail-bled and serum was prepared and analyzed to confirm low calcium concentrations.
Antagonism of ergocalciferol and cholecalciferol by retinyl acetate (Expt. 1). After depletion of retinol and calciferol, rats were divided into groups (n = 5–6). They were fed the purified diet and placed on a 3-d oral dosing schedule. On d 1, rats were dosed with 0.1 mL oil containing 0, 11.4, 1720, or 3440 µg retinyl acetate. On d 2, rats were dosed with 0.1 mL oil containing 0 ng calciferol; 25.8, 51.6, or 77.4 ng ergocalciferol; or 25 ng cholecalciferol. Finally, on d 3, rats were given 0.1 mL oil containing the previously described amounts of vitamin E and vitamin K (11). The schedule was continued for 33 d after which rats were killed. Blood was collected for further analysis.
Antagonism of ergocalciferol and cholecalciferol by ATRA (Expt. 2). After retinol and calciferol depletion, rats were divided into groups (n = 6–7). They were given 0, 100, 200, or 400 µg ATRA/d in the diet. These diets were made fresh weekly. Rats also were placed on the following 3-d oral dosing schedule. On d 1, rats were not dosed. On d 2, rats were given 0.1 mL oil containing 0 ng calciferol, 25.8 ng ergocalciferol, or 25 ng cholecalciferol. On day 3 rats were dosed with 0.1 mL oil containing the previously described amounts of vitamins E and K (11). The administration of ATRA diets in combination with oral dosing was continued for 33 d. During this time, groups were pair-fed so that food intake was similar for all rats. After 33 d, rats were killed and blood was collected for analysis.
Antagonism of 1,25(OH)2D3 and 24-F2-1,25(OH)2D3 by ATRA (Expts. 3 and 4). After retinol and calciferol depletion, rats were divided into groups (n = 6–8). Rats were fed 0, 20, or 400 µg ATRA/d in combination with 0, 2, 2.5, 5, or 10 ng 1,25(OH)2D3/d or 0, 0.5, 1, or 2.5 ng 24-F2-1,25(OH)2D3/d. ATRA, 1,25(OH)2D3, and 24-F2-1,25(OH)2D3 were all administered in the diet. Food intake was monitored and rats were fed only as much diet as would be completely consumed by all members of a group. Diets were prepared fresh weekly and were administered for 33 d. At the end of this period, rats were killed and blood was collected for analysis.
Serum calcium and phosphorus. Blood samples were centrifuged at 1096 x g for 15 min at room temperature using a Microfuge R centrifuge (Beckman). Serum was transferred to a new tube and stored at –20°C. Serum calcium concentrations were determined using atomic absorption spectrophotometry (27) and phosphorus concentrations were determined as previously described (28).
Serum 1,25(OH)2D3. Control serum samples were spiked with 16,000 dpm [26,27-3H]-1,25(OH)2D3 (163 Ci/mmol) and processed as normal samples to determine the percentage of radioactivity recovery from extractions. Briefly, 0.7 mL serum was extracted with an equal volume of ethyl acetate for 30 min, with mixing on a vortex every 5 min. Extracts were centrifuged at 701 x g for 10 min and the organic (upper) layer was removed to a fresh tube. The remaining material was extracted twice more with 0.5 mL ethyl acetate using an incubation time of 10 min, again mixing on a vortex every 5 min. The organic layers were pooled and dried down under N2 in a 37°C waterbath. The sides of the tube were rinsed with 1 mL ethanol and samples were dried down under N2 in a 37°C waterbath. Each sample was resuspended in 25 µL ethanol and allowed to equilibrate overnight at –20°C. Serum 1,25(OH)2D3 concentrations were measured as previously described (29).
Statistical analysis. SAS version 8 (SAS Institute) was used to analyze the data using a mixed procedure (Proc Mixed). Treatment groups were compared using contrasts. Differences with a value of P < 0.05 were considered significant.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Antagonism of ergocalciferol and cholecalciferol action by retinyl acetate (Expt. 1).
Rats administered 25.8 ng ergocalciferol in the absence or presence of a sufficient amount of retinyl acetate maintained normal serum calcium concentrations when fed a diet containing normal amounts of calcium and phosphorus. However, high but not toxic amounts of retinyl acetate inhibited the ability of 25.8 ng ergocalciferol to maintain these serum calcium concentrations (Table 1). Higher serum phosphorus concentrations accompanied the decreased serum calcium concentrations (Table 1). This antagonistic effect was limited, however, because higher amounts of retinyl acetate did not inhibit the ability of 
51.6 ng ergocalciferol to maintain serum calcium concentrations (Table 2). Serum phosphorus concentrations were lower in the groups that were not administered retinyl acetate (Table 2).
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100 µg ATRA/d in combination with 25.8 ng ergocalciferol or 25 ng cholecalciferol every 3 d had significantly lower serum calcium concentrations than rats not fed ATRA. As observed previously, this decrease in serum calcium concentrations occurred in conjunction with an increase in serum phosphorus concentrations (Table 4). Unlike retinyl acetate, ATRA suppressed serum calcium concentrations and increased serum phosphorus concentrations in ergocalciferol- and cholecalciferol-treated rats with equal efficiency (Table 4).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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51.6 ng ergocalciferol. Interestingly, retinyl acetate was more efficient in antagonizing the action of ergocalciferol than cholecalciferol. These 2 compounds are metabolized in a slightly altered manner due to differences in their structure (30). Therefore, it is possible that retinol has a more severe effect on ergocalciferol action due to these differences in metabolism. We attempted to measure the serum 1,25(OH)2D3 concentrations of cholecalciferol-treated rats administered increasing concentrations of retinyl acetate because decreased synthesis or increased destruction of 1,25(OH)2D3 is one possible explanation for the antagonistic activity of retinol. However, the concentrations of 1,25(OH)2D3 in the serum of these rats were below the detection limit of 12 pmol/L. Because low concentrations of cholecalciferol were used to observe retinol antagonism of calciferol action, this result was not surprising.
Not only retinyl acetate, but also ATRA, an active metabolite of retinol, inhibited the ability of both ergocalciferol and cholecalciferol to maintain serum calcium concentrations in rats fed a normal calcium and phosphorus diet (Expt. 2). As previously observed, this decrease in serum calcium concentrations was accompanied by an increase in serum phosphorus concentrations in these rats. Because ATRA is the form of retinol that regulates retinol-regulated gene transcription, the fact that ATRA antagonizes the action of ergocalciferol and cholecalciferol suggests that retinol is interfering with calciferol action at the molecular level.
Unlike retinyl acetate, ATRA was equally effective in suppressing ergocalciferol and cholecalciferol action. This may be due to the increased amount of ATRA circulating in the rats when they were fed ATRA as opposed to retinyl acetate.
To test whether ATRA may be acting on the enzymes that produce 1,25(OH)2D3, the biologically active form of calciferol, rats were fed ATRA in combination with 1,25(OH)2D3 (Expt. 3). ATRA inhibited the ability of 1,25(OH)2D3 to maintain serum calcium concentrations, thus indicating that ATRA was not acting on either the cholecalciferol-25-hydroxylase or the 25-hydroxycalciferol-1-hydroxylase enzyme.
As with ergocalciferol, ATRA was able to suppress the action of 1,25(OH)2D3 only when rats were administered 
5 ng 1,25(OH)2D3/d. When rats were given 10 ng 1,25(OH)2D3/d, the antagonistic response to ATRA administration was eliminated.
Finally, to investigate the possibility that ATRA was affecting the enzyme that deactivates 1,25(OH)2D3, 25-hydroxycalciferol-24-hydroxylase, rats were fed 24-F2-1,25(OH)2D3 in addition to ATRA (Expt. 4). 24-F2-1,25(OH)2D3 cannot be 24-hydroxylated and is assumed to be more potent than 1,25(OH)2D3 because it has a longer biological half-life (31). ATRA inhibited the ability of 24-F2-1,25(OH)2D3 to maintain serum calcium concentrations, suggesting that the antagonistic reaction was not due to ATRA affecting the 24-hydroxylase route of degradation, the major pathway of degradation of calciferol (32).
This result appears to be at odds with the finding that ATRA, 9CRA, an RAR-specific ligand, TTNPB, and an RXR-specific ligand, L100268, increased expression of 24-hydroxylase mRNA in the calciferol-sufficient mouse after 8 h of administration (24). A similar result was reported in a second study that demonstrated an increase in 24-hydroxylase activity in rats administered 9CRA and 1,25(OH)2D3 for 18 h (33). However, in the first study, when L100268 and 1,25(OH)2D3 were administered simultaneously for 8 d to calciferol-depleted mice, 1,25(OH)2D3-stimulated expression of 24-hydroxylase mRNA was suppressed. The difference in the 2 results found in the first study was hypothesized to occur because in the short term, retinoids increased 24-hydroxylase concentrations leading to a decrease in 1,25(OH)2D3 concentrations; over a longer period of time, this produced a decrease in 1,25(OH)2D3-stimulated gene expression, including 24-hydroxylase gene expression. This theory also may account for the differences observed in the findings of the 2 previously reported studies and some of the results presented above, but cannot account for the fact that ATRA inhibited 24-F2-1,25(OH)2D3 action because this analog is not 24-hydroxylated. Therefore, it appears that the antagonism demonstrated here in vivo is not related to the 24-hydroxylase studies of Allegretto et al. (24) and Reinhardt et al. (33) but instead is more likely related to the molecular action of calciferol compounds on transcription or another mechanism of antagonism.
A measurement of serum 1,25(OH)2D3 concentrations would test directly whether retinyl acetate and ATRA antagonize calciferol action by interfering with either the production or destruction of 1,25(OH)2D3. Unfortunately, due to the necessity of using small doses of calciferol and 1,25(OH)2D3 to observe this antagonistic action of retinol, 1,25(OH)2D3 concentrations were below the detection limits of currently available assays and kits when rats were administered 25.8 ng cholecalciferol every 3 d. Furthermore, based on the experience of our laboratory and calculations estimating the amount of 1,25(OH)2D3 that should be present in the serum of a 350- to 450-g rat given 2.5 ng 1,25(OH)2D3/d in the diet, serum 1,25(OH)2D3 concentrations in these rats are 12–19 pmol/L, the detection limit of the assay. Therefore, measurement of serum 1,25(OH)2D3 concentrations of these rats is not feasible at this time.
Together, the results presented above suggest that retinol antagonizes calciferol action through another mechanism of action and not by affecting the activity of the calciferol-metabolizing enzymes, although effects on the 24-hydroxylase enzyme are nevertheless possible. This hypothesis rests largely on the fact that ATRA antagonizes the action of 24-F2-1,25(OH)2D3, a compound that cannot be 24-hydroxylated. Another possible method of antagonism is that ATRA could be affecting 1,25(OH)2D3-regulated gene expression. Because both retinol and calciferol require RXR to carry out regulation of gene expression through their active metabolites, high amounts of retinol may act by sequestering RXR protein through the formation of RAR-RXR heterodimers and/or RXR-RXR homodimers and hence inhibit formation of VDR-RXR heterodimers. Another way in which 1,25(OH)2D3-mediated gene expression could be affected is through the formation of inactive 9CRA-bound RXR-VDR heterodimers. However, other possible mechanisms of antagonism such as an effect on calciferol absorption, an effect on calciferol transport proteins, or a calciferol-independent effect cannot be ruled out.
In conclusion, retinol weakly antagonizes calciferol action but does not do so by affecting the metabolism of calciferol or its active metabolite 1,25(OH)2D3 through the CYP24 pathway.
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FOOTNOTES |
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3 Abbreviations used: ATRA, all-trans retinoic acid; 9CRA, 9-cis retinoic acid; CYP, cytochrome P450; 24-F2–1,25(OH)2D3, 24,24-difluoro-1,25-dihydroxycholecalciferol; 1,25(OH)2D3, 1,25-dihydroxycholecalciferol; PTH, parathyroid hormone; RAR, retinoic acid receptor; RXR, retinoid X receptor; VDR, vitamin D receptor.
Manuscript received 14 October 2004. Initial review completed 9 December 2004. Revision accepted 24 April 2005.
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