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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-2750
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 7 2612-2617
Copyright © 2006 by The Endocrine Society

Vitamin D Metabolism in Peripheral Blood Mononuclear Cells Is Influenced by Chewing "Betel Nut" (Areca catechu) and Vitamin D Status

William B. Ogunkolade1, Barbara J. Boucher1, Stephen A. Bustin, Jacky M. Burrin, Kate Noonan, Nasima Mannan and Graham A. Hitman

Centers for Diabetes and Metabolic Medicine and Academic Surgery, Institute of Cell and Molecular Science (W.B.O., B.J.B., S.A.B., N.M., G.A.H.), and Clinical and Molecular Endocrinology, William Harvey Institute (J.M.B.), Queen Mary’s School of Medicine and Dentistry, University of London and Department of Clinical Chemistry (K.N.), Barts and The London National Health Service Trust, Royal London Hospital, London E1 1BB, United Kingdom

Address all correspondence and requests for reprints to: Graham A. Hitman, M.D., Center for Diabetes and Metabolic Medicine, Royal London Hospital, London E1 1BB, United Kingdom. E-mail: g.a.hitman{at}qmul.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Vitamin D deficiency, common in South Asians, is a risk factor for metabolic syndrome, type 2 diabetes, and ischemic heart disease. Vitamin D receptor (VDR) activation depends on activated vitamin D [1,25-dihydroxyvitamin D (1,25(OH)2D)] concentration, reflecting opposing actions of 25-hydroxyvitamin D-1{alpha}-hydroxylase [1-{alpha}(OH)ase] for formation and 25(OH)D-24-hydroxylase [24(OH)ase] for catabolism. We previously reported that circulating 1,25(OH)2D contributed to determination of VDR-protein levels and VDR genotype was a determinant of both VDR mRNA and VDR-protein in South Asians.

Objective: We hypothesized that chewing betel nut, an addictive habit common throughout South Asian communities, contributes to hypovitaminosis-D by modulating the enzymes regulating circulating 1,25(OH)2D concentration.

Design: Peripheral blood mononuclear cell (PBMC) 1-{alpha}(OH)ase and 24(OH)ase mRNA concentrations were measured and examined in relation to cross-sectional data on the vitamin-D axis, diet, smoking, and betel usage, including PBMC VDR-RNA and VDR-protein content in a pilot study of 33 healthy British Bangladeshis.

Results: PBMC 24(OH)ase mRNA correlated positively and serum 1,25(OH)2D negatively with betel quids per day (r = 0.49, P = 0.006 and r = –0.486, P = 0.006, respectively). Independent determinants for 24(OH)ase included betel quids per day (P < 0.0001) and serum 25-OHD (P = 0.024). Independent determinants for serum 1,25(OH)2D were gender, smoking, and betel quids per day. PBMC 1-{alpha}(OH)ase mRNA correlated inversely with VDR mRNA (r = –0.44; P = 0.013); its independent determinants were serum 1,25(OH)2D and VDR TaqI and BsmI polymorphisms (P = 0.03–0.0001).

Conclusions: Betel chewing is a more powerful independent determinant of increased 24(OH)ase expression and of decreased serum calcitriol than serum 25-OHD, supporting the hypothesis that this habit could aggravate the effects of vitamin-D deficiency.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
VITAMIN D, WHETHER DIETARY or formed in the skin by UV radiation, is hydroxylated to 25-hydroxyvitamin D (25-OHD) in the liver and, once bound to circulating vitamin D binding proteins, has a half-life of several weeks (1, 2). Serum levels of 25-OHD are accepted as reflecting vitamin D "status" (3, 4). Activation of 25-OHD by 25-hydroxyvitamin D-1{alpha}-hydroxylase [1-{alpha}(OH)ase] to form hormonal vitamin D [1,25-dihydroxyvitamin D; calcitriol (1,25(OH)2D)] was first thought to take place solely in the kidney but is now recognized in many extrarenal tissues (5). Tissues such as circulating monocytes [peripheral blood mononuclear cells (PBMCs)], pancreatic islets, vascular wall, brain, colon, and breast express both the 1-{alpha}(OH)ase enzyme and the vitamin D receptor (VDR) and, in addition, the enzyme 25(OH)D-24-hydroxylase [24(OH)ase] that inactivates 1,25(OH)2D and probably also 25-OHD (5, 6). Circulating PTH contributes to the up-regulation of renal 1-{alpha}(OH)ase activity, and its secretion itself is suppressed by 1,25(OH)2D, providing a feedback mechanism, reducing the risk of vitamin D toxicity (1, 2). However, it is not believed that PTH affects 1-{alpha}(OH)ase expression directly in other tissues such as the PBMC, even though macrophages produce hormonally active vitamin D. Furthermore, locally produced 1,25(OH)2D will recruit monocytes into the differentiation process, leading to increased macrophage production, as demonstrated in monocyte culture (7), although the mechanisms regulating these extrarenal processes are yet to be understood fully (8).

The "classical" actions of vitamin D ensure the maintenance of calcium and phosphate homeostasis and of adequate bone ossification (1, 2), but the "nonclassical" actions of vitamin D affect many other tissues in humans. These include pancreatic islet insulin secretion, insulin resistance, the immune system, and the induction of cellular differentiation (9, 10, 11, 12, 13, 14). Such nonclassical actions may explain why vitamin D deficiency is linked to increased cancer risks in many organs where the VDR is expressed (e.g. breast, colon, ovary, and prostate) as well as associations with other conditions (13, 14).

Vitamin D deficiency is also associated with increased risk, and severity, of chronic inflammatory disorders including tuberculosis and leprosy (15, 16) and, in early life, with increases in autoimmune disorders such as type 1 diabetes in childhood and early adult life (17, 18, 19, 20). These phenomena may reflect reductions in the monocyte activation and differentiation into macrophages and dendritic cells induced by activated vitamin D, as found in vitro (6, 7, 8). During this differentiation VDR expression falls, whereas that of the 1-{alpha}(OH)ase increases (7), suggesting that VDR expression in healthy PBMCs should be inversely related to expression of the 1-{alpha}(OH)ase when examined in subjects of varying vitamin D status.

Vitamin D deficiency remains common in Indian Asian immigrants and their descendants, but is also seen in healthy South Asians living in sunny climates (9, 10, 11, 21, 22). Most studies attribute the high prevalence of vitamin D deficiency to cultural and dietary habits. In addition, an alteration in vitamin D metabolism has been postulated recently in South Asians after the finding of increased 24(OH)ase activity in skin fibroblasts in American South Asians compared with American white subjects (23). This increase in 24(OH)ase would be expected to lead to increased catabolism of the active metabolite 1,25(OH)2D and perhaps of 25-OHD, worsening the effects of hypovitaminosis D. Failure of British South Asians to respond fully to supplementation (24) may be explained by this finding. We have previously shown, in British South Asians, that circulating levels of calcitriol [hormonal vitamin D; 1,25(OH)2D] contribute to the determination of VDR protein levels in vivo and, in addition, that VDR genotype is a significant determinant of both VDR mRNA and protein levels in PBMCs (25). Because production of activated vitamin D is increased in vitamin D deficiency (1, 2, 26), it is likely that VDR genotype contributes to the feedback control mechanism determining vitamin D activation. Therefore, we have hypothesized that the clinical effects of this deficiency could be influenced by genetic, environmental, or dietary factors specific to this population.

An obvious candidate is the addictive habit of betel chewing. Nuts of the Areca catechu palm are wrapped in leaves of the Piper betle vine, usually spread with lime paste, to form quids, or "chews" (sometimes called "pan" or "paan"). In some communities (including our local Bangladeshi population living in East London) tobacco is also added. This is the fourth most common addictive habit worldwide after smoking, caffeine, and alcohol, and is estimated to be used by 600 million people worldwide (27). The effects of betel chewing on vitamin D metabolism or calcium homeostasis are unknown, although there is one case report of hypercalcemic alkalosis after long-term daily consumption of 40 betel quids (containing lime paste rich in calcium hydroxide) (28). Pilot studies were set up to determine whether in vivo expression of 1-{alpha}(OH)ase and 24(OH)ase genes relate to VDR gene expression, using circulating PBMCs from healthy subjects, as a reflection of the induction of differentiation of macrophages from monocytes (7). We also aimed to determine whether vitamin D status (serum 25-OHD), circulating PTH, or VDR polymorphisms affect 1-{alpha}(OH)ase or 24(OH)ase gene expression in the PBMC or, in particular, whether vitamin D metabolism in the PBMC is affected by dietary habits common in South Asians such as chewing "betel nut" (Areca catechu) (27).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Forty-one healthy British Bangladeshi subjects, aged 31–65 yr, living in East London, free of ongoing illness, and on no long-term medication gave written informed consent to provision of a blood sample for an embedded cross-sectional study of the vitamin D axis during a study of vitamin D insufficiency in relation to risk factors for type 2 diabetes and ischemic heart disease (29, 30). These studies were approved by the appropriate District Ethical Committee. Thirty-six percent of the subjects were men. Data from a previously validated questionnaire were available on smoking, betel nut (paan quid) usage, and the intake of fish (several species of imported freshwater fish that are vitamin D rich, and fish being eaten daily by >40% of subjects; average 5.5 times per week), eggs (averaging 60 U each in the United Kingdom; Boucher, B. J., N. Mannan, and K. Noonan, unpublished data), yogurt (sometimes fortified in the United Kingdom), and margarine (fortified by statute in the United Kingdom) (10, 29). VDR genotype (ApaI, BsmI, TaqI, and FokI) had also been determined, as previously reported, in this subgroup (30).

RNA extraction and real-time quantitative RT-PCR analysis

Total cellular RNA was extracted from untreated PBMCs, as for the VDR, as previously reported, from 107 PBMCs using the RNeasy mini RNA isolation kit (QIAGEN Inc., Crawley, UK). RNA quality was assessed using RNA LabChips on an Agilent 2100 Bioanalyser (Agilent Technologies, Waldbronn, Germany) and quantified in triplicate, using Ribogreen quantification kits (Molecular Probes, Leiden, The Netherlands). PBMC VDR mRNA and VDR protein levels in these subjects were measured in extracts from 107 cells as reported previously (25).

1-{alpha}(OH)ase mRNA and 24(OH)ase mRNA were measured by quantitative real-time polymerase chain reaction (qRT-PCR) in PBMCs as follows. Sequence-specific primers and probes (Table 1Go) were designed using Primer Express (Applied Biosystems, Warrington, UK), and synthesized by Applied Biosystems or Proligo (Paris, France). The TaqMan probe was labeled with a reporter dye (6-carboxy-fluorescein) at the 5' end and a quencher dye (6-carboxy-tetramethyl-rhodamine) at the 3' end. qRT-PCR was performed with 50-ng (in duplicate) aliquots of RNA, from the same cells that had previously been used to quantify VDR mRNA and VDR protein levels (25), using an ABI Prism 7700-sequence detector (Applied Biosystems, Warrington, Cheshire, UK), or Stratagene MX4000 (Stratagene, La Jolla, CA), and analyzed with the corresponding manufacturer-supplied software. mRNA copy numbers were determined from a specific standard curve obtained by serially diluting a synthetic single-stranded sense oligonucleotide specifying the 1-{alpha}(OH)ase or 24(OH)ase amplicon (31). There was a strong linear relationship between the threshold cycle and the log of the starting RNA-copy number in all runs (r > 0.99; Table 1Go). All serial dilutions were carried out in duplicate. Standard curves in triplicate were repeated twice with duplicate no-template controls included with every RT-PCR run. Copy numbers were normalized relative to total RNA concentration, and the levels were expressed as mRNA copy numbers per microgram of total RNA (32).


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  		TABLE 1. Formulae for forward (F) and reverse (R) primers and probes (P) used for the measurement of the expression of the target genes for the two vitamin D metabolic enzymes studied and for the vitamin D receptor

 
Immunoassays

Serum 25-OHD [<20 ng/ml (<50 nmol/liter) defining vitamin D insufficiency (4)] and 1,25(OH)2D [normal range for adults 20–46 pg/mol (48–110 pmol/liter)] and serum intact PTH concentration [normal range 430-1070 pg/ml (48–119 pmol/liter)] were measured by immunoassay in single assays (IDS Ltd., Boldon, Tyne and Wear, UK; intraassay coefficient of variation < 7%) as previously reported (29). Information on insulin secretory profiles and glycemia at oral glucose tolerance test within the parent study was also available together with calculated "insulin secretion index" derived from data at 75-g oral glucose tolerance testing (33).

Statistical analyses

Simple and partial correlation coefficients and variation of means with VDR polymorphisms were examined using parametric or nonparametric tests as appropriate and stepwise multiple regression analysis was carried out (to P < 0.05), after normalization of data distribution where necessary, using SPSS version 11. Results are given as mean ± SD in the text and tables and as mean ± SE in Fig. 1Go.


Figure 1
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  		FIG. 1. mRNA expression (copy numbers per microgram of total RNA) of the 24(OH)ase gene in fresh blood mononuclear cells in six nonchewers and in subjects chewing increasing numbers of betel nut quids per day.

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 2Go shows the main demographic details and data for dietary factors examined in the study subjects. Table 3Go shows the mean (SD) and ranges for serum 25-OHD, 1,25(OH)2D, and for PBMC content of 1-{alpha}(OH)ase mRNA and 24(OH)ase mRNA. The data reported for VDR mRNA and VDR-protein in these PBMC preparations (25) are those for the subjects in whom sample volumes were adequate for measurement of PBMC 1-{alpha}(OH)ase mRNA (n = 33 of 41) and 24(OH)ase mRNA (n = 31 of 41).


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  		TABLE 2. Age, body mass index (BMI), smoking habits, rate of chewing paan (betel nut) quids, percentage of chewers adding chewing tobacco to the quids, and data for the consumption of the major United Kingdom South Asian dietary sources of vitamin D (eggs, imported fresh water fish, and the percentage of subjects using margarine) for the 41 subjects in the embedded cross-sectional study

 

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  		TABLE 3. Concentrations of 25-OHD and 1,25(OH)2D in serum and PBMC concentrations of VDR mRNA, VDR protein, 1-{alpha}(OH)ase mRNA, and 24(OH)ase mRNA in subjects included in the present study

 
There were more women than men in the study group, but there was no variation in 24(OH)ase expression with gender. In addition, men smoked more cigarettes per day than women, but smoking rates did not vary with rates of betel chewing.

Simple correlation analysis showed that the expression of 1-{alpha}(OH)ase mRNA was inversely correlated with that of VDR mRNA (n = 33, r = –0.44; P = 0.013).

The independent determinants of 1-{alpha}(OH)ase mRNA expression, by multiple regression analysis (Table 4Go), were circulating 1,25(OH) together with VDR (TaqI and BsmI) polymorphisms but not serum PTH or any of the other factors examined. When 24(OH)ase mRNA concentrations were included in this analysis, the independent determinants of 1-{alpha}(OH)ase mRNA were the VDR (TaqI and ApaI) polymorphisms (P < 0.0001 and 0.006, respectively) and serum 25-OHD (P = 0.048) as well as the PBMC content of 24(OH)ase mRNA (P = 0.001), although this was not the best-fit model (P for the constant <0.0001); because VDR genotype contributes to the determination of VDR message and protein in these subjects (25), this analysis was repeated omitting VDR mRNA content but the findings were not changed; omitting VDR-protein content revealed betel quids per day as the sole determinant of 1-{alpha}(OH)ase mRNA expression, and no determinants of 1-{alpha}(OH)ase mRNA were identified when both VDR mRNA and VDR-protein concentrations were omitted from the analysis.


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  		TABLE 4. Multiple regression analysis for the determinants of gene expression for the enzymes 25(OH)D-1-{alpha}-hydroxylase (activating vitamin D) and 25(OH)D-24-hydroxylase [catabolizing 1,25(OH)2D] in PBMC

 
The expression level of 24(OH)ase mRNA in PBMCs was higher, although not significantly, in chewers (n = 25) than in never-chewers (n = 6) [mean(SD) = 40.5 x 105 (24.3 x 105) compared with 55.2 x 105 (43.2 x 105); P = 0.43], but was directly correlated with the number of paan (betel) quids eaten daily [r = 0.49; P = 0.006 and 0.71, P < 0.0001 by partial correlation, allowing for serum 25-OHD and 1,25(OH)2D] as illustrated by the raw data in Fig. 1Go. Serum 25-OHD was not related to betel quids per day. Serum 1,25(OH)2D correlated negatively with the number of paan (betel) quids eaten daily (r = –0.43, P = 0.006; Fig. 2Go).


Figure 2
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  		FIG. 2. Residual plot showing the relation of serum 1,25(OH)2D concentration to numbers of betel quids chewed per day in five nonchewers and in subjects chewing increasing numbers of betel nut quids per day as revealed by multiple regression analysis (see Table 4Go for the findings for determinants of the PBMC content of 24(OH)ase mRNA).

 
The independent determinants for 24(OH)ase mRNA (Table 4Go) included betel quids per day and serum 25-OHD when 1-{alpha}(OH)ase was included in analysis, but betel quids per day alone when 1-{alpha}(OH)ase was excluded. Betel quids per day was a less powerful determinant of serum 1,25(OH)2D than gender or cigarettes smoked per day (data not shown); the latter was inversely correlated to serum PTH on Spearman ranking (r = –0.28, P < 0.0001 for the parent group and r = –0.3, P = 0.049 in the current study subgroup). The inclusion of data on the addition of chewing tobacco to paan quids did not affect the significance of any of the findings.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We have found a direct correlation between 25-OHD-24(OH)ase expression and the rates of use of betel quid (paan) chews containing Areca catechu nut in the present cross-sectional study. The finding of dose-effects for this relationship and that the relationship is independent of other factors known to regulate 24(OH)ase expression suggests that, despite the cross-sectional nature of the study, betel chewing may explain the increases in tissue activity of 24(OH)ase, the rate-limiting enzyme for degradation of 1,25(OH)2D, reported in South Asians, even though they were vitamin D deficient (23). This is a surprising finding because induction of the 24(OH)ase gene in the presence of increased vitamin D availability is a recognized part of the feedback mechanisms preventing vitamin D intoxication. This enzyme is catabolic for both activated vitamin D and its immediate precursor 25-OHD. The biological effects of vitamin D inadequacy could, therefore, be aggravated by betel chewing in vitamin D deficiency.

Compared with white Caucasians, South Asians in the West and Northern world have a higher prevalence of vitamin D deficiency than white Caucasians (10, 12, 15, 23). This deficiency has been implicated as a risk factor for various diseases including diabetes, ischemic heart disease, and tuberculosis. We have previously shown, in the subjects of the present study, that the circulating level of activated vitamin D [1,25(OH)2D] is a predictor of VDR protein in the PBMC and that VDR mRNA and VDR protein levels in circulating PBMCs also predict variations in insulin secretion index, in vivo, as assessed at oral glucose tolerance test (25, 30). We now observe that 1-{alpha}(OH)ase mRNA concentration in PBMCs is inversely correlated to that of VDR mRNA, in vivo. Because PBMC differentiation in vitro has been shown to be associated with decreasing expression of VDR mRNA and increasing expression of 1-{alpha}(OH)ase mRNA (7), these findings suggest that the biological processes of PBMC differentiation in vivo are similar to those identified in vitro. This is supported by our finding that circulating hormonal vitamin D [serum 1,25(OH)2D concentration] rather than vitamin D status (serum 25-OHD concentration) contributed to the determination of PBMC 1-{alpha}(OH)ase expression on multiple regression analysis.

Although the regulation of the 1-{alpha}(OH)ase and 24(OH)ase genes in PBMCs is not yet fully defined (34, 35, 36), defects in up-regulation of macrophage 1-{alpha}(OH)ase expression in response to immune stimuli have been shown to contribute to the development of type 1 diabetes in autoimmune nonobese diabetic mice (36). Such defects, whether inherent or as a result of vitamin D deficiency, will reduce the availability of activated vitamin D in target tissues leading to decrease in both macrophage differentiation and recruitment from circulating monocytes (7). The increased risks of chronic inflammatory disorders, metabolic syndrome, and autoimmune disorders reported in South Asians and others with vitamin D deficiency could well be aggravated by the effects of betel chewing on 24-(OH)ase, and the reductions in risk of type 1 diabetes reported after early life supplementation with vitamin D in white Caucasians could also be diminished in betel chewers (18, 19, 20).

Betel chewing is common among South Asian populations; it is the fourth most common habit after smoking, alcohol, and caffeine, and is estimated to be practiced by 600 million people globally (27). The mutagenic, genotoxic, and carcinogenic properties of betel nut (Areca catechu) extracts are well established (27). The fact that we have found betel usage to be a more powerful independent determinant of 24(OH)ase expression than vitamin D status in these subjects on multiple regression analysis (standardized coefficient of correlation 0.72 vs. 0.34) suggests that this effect should be further investigated because such large proportions of the world population chew betel nut and are liable to vitamin D deficiency (4, 21, 22, 27, 28, 37). An association between consumption of betel nut and hyperglycemia has been reported experimentally (38) and similar associations have recently been reported in humans (39, 40), including dose-response effects in a large population-based study (40). Suggested mechanisms responsible for the association of the chewing of Areca catechu (betel) nut with disease include glutathione depletion, generation of free radicals, mitochondrial dysfunction, disturbance of the cell cycle, induction of apoptosis, and DNA damage (27). The actions of Arecal alkaloids, including {gamma}-aminobutyric acid receptor blockade, have been widely studied, and Arecal nitrosamine derivatives are accepted as being carcinogenic in the human by the International Agency for Research on Cancer (27). Furthermore, drugs known to induce vitamin D deficiency such as rifampicin and carbemazipine recently have been shown to up-regulate expression of the 24(OH)ase gene through activation of the nuclear pregnane X receptor both in the human hepatocyte and, experimentally, in vivo, with increases in circulating 24,25-dihydroxyvitamin D (41). Therefore, it is possible that the ingestion of Arecal alkaloids, nitrosation adducts, or other components of betel chews might have a similar effect.

In conclusion, these preliminary data demonstrate that 1-{alpha}(OH)ase gene expression in circulating PBMCs relates inversely to VDR expression in humans, matching previous in vitro observations that hormonal vitamin D increases 1-{alpha}(OH)ase gene expression in PBMCs. This supports previous suggestions as to how monocyte activation (and thus macrophage efficacy) may be reduced in vitamin D deficiency (7). These preliminary findings also support the hypothesis that the habit of chewing betel (paan quids containing Areca catechu nut) could reduce the availability of active vitamin D by dose-dependent increases in expression of the 24(OH)ase enzyme catabolic for activated vitamin D. Further investigation of these phenomena would be useful because, if confirmed, they provide mechanisms that could contribute to the explanation of the increased risk of chronic inflammatory and autoimmune disorders found in hypovitaminosis D and also to the increased 24(OH)ase enzyme activity reported in South Asians and thus to the particular severity of vitamin D deficiency in South Asian populations.


   Acknowledgments
 
The authors thank Dr. D. Syndercombe-Court for advice and assistance with PBMC preparation, Prof. H. DeLuca and Dr. J. Prahl for permission to reexamine the PBMC VDR-protein data, and M. F. McDermott and E. Aganna for VDR genotyping.


   Footnotes
 
Grants from Diabetes UK and the North-East Thames (now "North Thames") R and D Directorate of the National Health Service contributed to the support of this work.

First Published Online May 2, 2006

1 W.B.O. and B.J.B. are joint first authors. Back

Abbreviations: 1-{alpha}(OH)ase, 25-Hydroxyvitamin D-1{alpha}-hydroxylase; 24(OH)ase, 25(OH)D-24-hydroxylase; 25-OHD, 25-hydroxyvitamin D; 1,25(OH)2D, 1,25-dihydroxyvitamin D (calcitriol); PBMC, peripheral blood mononuclear cell; VDR, vitamin D receptor.

Received December 16, 2005.

Accepted April 24, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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