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PubMed2001

The effect of season and vitamin D supplementation on bone mineral density in healthy women: a double-masked crossover study.

Vitamin D status is known to be an important determinant of bone mineral density (BMD). There is a significant seasonal variation in serum vitamin D, and some studies have reported an associated seasonal variation in BMD. The present study was devised to investigate whether a seasonal variation in BMD could be detected in healthy normal subjects, along with associated variations in serum parathyroid hormone (PTH), intestinal calcium absorption and biochemical markers of bone turnover. A second aim was to investigate whether, if such variations were identified, they could be suppressed by vitamin D supplementation. The subjects were 70 healthy female volunteers (mean age 47.2 years, range 24-70 years) recruited into a double-masked crossover study and followed over 2 years. During the first year 35 subjects received a daily oral supplement containing 800 IU (20 micrograms) cholecalciferol (group 1) and 35 subjects received a placebo preparation (group 2). During the second year the treatment each group received was reversed. Lumbar spine (L1-L4), left proximal femur and total body BMD were measured by DXA at 3-month intervals. Serum 25-hydroxyvitamin D (25-OHD), serum PTH, bone markers (bone-specific ALP (BSAP) and urinary crosslinks (DYPD/creatinine)) and calcium absorption were also measured at each visit. Cholecalciferol treatment increased serum 25-OHD by 25.4 nmol/l (p < 0.001), while a reciprocal decrease in serum PTH of 6.6 ng/l (p = 0.011) was seen in subjects in the lowest quartile of baseline serum 25-OHD. The treatment had no significant effect on spine, femur or total body BMD, calcium absorption or bone markers. When Fourier analysis was used to analyze the data for seasonal effect (defined as twice the amplitude of the 1-year period variation) a highly significant effect for 25-OHD of 18 nmol/l (p < 0.001) was found. However, no effect was found for BMD, PTH, calcium absorption or bone markers. The analysis set a 95% confidence limit to the seasonal effect of less than 0.6% for spine, total hip and total body BMD. It was concluded that in the population of healthy women studied there was no evidence of seasonal variation in spine, femur or total body BMD, serum PTH, calcium absorption or bone markers. Vitamin D supplementation was found to have no effect on BMD.

Adult↗
PubMed1984

Purification of cytochrome P-450 catalyzing 25-hydroxylation of vitamin D3 from rat liver microsomes.

Cytochrome P-450 catalyzing 25-hydroxylation of cholecalciferol (cytochrome P-450 cc25 ) was purified from rat liver microsomes based on its catalytic activity at each purification step. The specific cytochrome P-450 content of the final preparation was 15.1 nmol/mg of protein. Reconstituted activity of 25-hydroxylation of cholecalciferol with the purified enzyme was 2.3 nmol/min/mg of protein, which was 4,300 times as high as that in microsomes. The minimum molecular weight of the enzyme was 50,000 based on SDS-polyacrylamide gel electrophoretogram. Amino terminal sequence of the P-450 cc25 was H2N-Met-Asp-Pro-Val-Leu-Val-. Immunochemical study showed that the purified P-450 cc25 was homogeneous and the cytochrome was immunochemically different from either cytochrome P-450(PB-1) or cytochrome P-448(MC-1).

Amino Acid Sequence↗
PubMed1986

Characteristics of antisera to antigenic forms of 1,25-dihydroxycholecalciferol.

Antisera to 1,25-dihydroxycholecalciferol were raised to 1,25-dihydroxycholecalciferol 25-hemisuccinate-bovine serum albumin, 1,25-dihydroxycholecalciferol 3-hemisuccinate-bovine serum albumin, 1,25-dihydroxycholecalciferol 3-hemisuccinate-porcine thyroglobulin and (5Z,7E)-(1S,3R)-1,3 dihydroxy-9,10-seco-24,25, 26,27-tetrakisnor-5,7,10(19)-cholestatrien-23-oic acid porcine thyroglobulin in rabbits. The antisera cross-reacted with a wide spectrum of vitamin D metabolites but their affinity was highest for 1,25-dihydroxycholecalciferol and some differentiated between ergo- and cholecalciferol metabolites. The presence of vitamin D binding protein and the pH of incubation markedly affected the sensitivity and specificity of antisera. A number of antisera were capable of measuring the normal plasma concentrations of vitamin D metabolites and their different affinities could be used for the measurement of 1,25-dihydroxyergocalciferol and 1,25-dihydroxycholecalciferol in plasma. None however were specific enough for the direct measurement of the metabolites in plasma. Immunisation increased the plasma concentration of endogenous 1,25-dihydroxyergo- and cholecalciferol in the animals.

Antigen-Antibody Complex↗
PubMed1993

Vitamin D is a membrane antioxidant. Ability to inhibit iron-dependent lipid peroxidation in liposomes compared to cholesterol, ergosterol and tamoxifen and relevance to anticancer action.

Vitamin D is a membrane antioxidant: thus Vitamin D3 (cholecalciferol) and its active metabolite 1,25-dihydroxycholecalciferol and also Vitamin D2 (ergocalciferol) and 7-dehydrocholesterol (pro-Vitamin D3) all inhibited iron-dependent liposomal lipid peroxidation. Cholecalciferol, 1,25-dihydroxycholecalciferol and ergocalciferol were all of similar effectiveness as inhibitors of lipid peroxidation but were less effective than 7-dehydrocholesterol; this was a better inhibitor of lipid peroxidation than cholesterol, though not ergosterol. The structural basis for the antioxidant ability of these Vitamin D compounds is considered in terms of their molecular relationship to cholesterol and ergosterol. Furthermore, the antioxidant ability of Vitamin D is compared to that of the anticancer drug tamoxifen and its 4-hydroxy metabolite (structural mimics of cholesterol) and discussed in relation to the anticancer action of this vitamin.

Animals↗
PubMed1996

Glutathione plays a role in the chick intestinal calcium absorption.

DL-buthionine-S,R-sulfoximine (BSO) administration to vitamin D-deficient chicks treated with cholecalciferol produces a rapid decrease in the Ca2+ transfer from lumen-to-plasma and in the intestinal glutathione content. This response was reversed by addition of glutathione monoester to the intestinal sac. Variables related to the Ca2+ homeostasis such as plasma Ca and P, and intestinal calbindin D28k were not modified by BSO given to vitamin D-deficient chicks treated with cholecalciferol. Intestinal alkaline phosphatase activity, on the contrary, was highly reduced by BSO in vitamin D-deficient chicks treated with vitamin D3. This effect showed time and dose-dependency. Although the mechanism/s of action of BSO on the intestinal Ca absorption is unknown, it is quite possible that thiol groups of protein involved in the Ca2+ transport are affected by the GSH depletion and/or by block of the antioxidant ability of vitamin D3. Thus, reactive oxygen compounds would be increased and, therefore, the Ca2+ movement from lumen to plasma decreases.

Alkaline Phosphatase↗
PubMed2005

Colon cancer and solar ultraviolet B radiation and prevention and treatment of colon cancer in mice with vitamin D and its Gemini analogs.

It has been recognized that people who live at higher latitudes and who are vitamin D deficient are at higher risk of dying from many common cancers including colon cancer. To evaluate the role of vitamin D deficiency on colon tumor growth, Balb/c adult male mice were fed either a vitamin D sufficient or vitamin D deficient diet for 10 weeks. Mice were arranged into groups of six and each animal received subcutaneously 10(4) MC-26 cells in the posterior trunk. The tumor size was recorded daily. By day 9 there was a significant difference in tumor volume between the vitamin D sufficient and vitamin D deficient mice. By day 18 the vitamin D deficient animals had a tumor size that was 56% larger compared to the animals that were vitamin D sufficient. To determine whether treatment with active vitamin D analogs could further decrease colon tumor growth in a vitamin D sufficient state, groups of mice were treated with the novel 19-nor-Gemini compounds. The mice were fed a low calcium diet. Twenty-four hours after tumor implantation, the mice received, three times weekly, one of the vitamin D analogs or the vehicle. The group that received Gemini 1,25-dihydroxy-21(3-hydroxy-3-trifluoromethyl-4-trifluoro-butynyl)-19-nor-20S-cholecalciferol (3) showed a dose-dependent decrease in tumor volume. On day 19, at the dose level of 0.02microg molar equivalents (E), the tumor volume was reduced by 41% when compared to the control group. At the same time point, the hexadeuterated analog 1,25-dihydroxy-21(3-hydroxy-3-trifluoromethyl-4-trifluoro-butynyl)-26,27-hexadeutero-19-nor-20S-cholecalciferol (4), administered at the 10-fold lower dose of 0.002microgE, showed a 52% reduction in tumor volume (p<0.05), compared to the control group. Animals that received 1,25(OH)(2)D(3) at 0.002 and 0.02microg showed a trend in tumor volume reduction at the highest dose but the changes were not statistically significant. An evaluation of serum calcium concentrations revealed that the calcium levels were normal in all groups, except the group receiving 0.02microgE of 4. The results from these studies demonstrate that vitamin D deficiency may accelerate colon cancer growth and that novel Gemini analogs of 1,25(OH)(2)D(3) may be an effective new approach for colon cancer treatment.

Animals↗
PubMed2000

Status of calcium and vitamin D of different population groups in Austria.

Vitamin D and calcium are essential for bone metabolism and the status of both nutrients is discussed in relation to osteoporosis and osteoporosis-related disorders. Thus, it is important to monitor the status of these nutrients in the population to early recognise insufficiences and to establish preventive measures. Intakes of calcium and vitamin D have been evaluated in different Austrian population groups (pre-school children, school children, adolescents, adults, elderly, pregnant and lactating women) by dietary records (3 d and 7 d weighed records, 24 h recalls). From pre-school children, school children, elderly, pregnant and lactating women fasting blood and spontaneous urine samples were collected and analysed on concentrations of calcium in serum and urine (adjusted to creatinine) and of 25-OH-cholecalciferol in serum. Average calcium intake (834 +/- 422 mg/d) below the specific recommended allowances of the according age group were found for 58% of the total population with the highest incidence of low supply in adolescents at 15-19 years of age and adults at 46-65 years of age. Vitamin D intakes (2.1 +/- 1.4 micrograms/d) were even lower with 68% of the total population being not able to meet the recommendations. Again, adolescents at 15-19 years showed the highest incidence of insufficient vitamin D intakes. Calcium concentrations in serum were satisfying for children and adolescents. Vitamin D status was found below the reference range (15 nmol/l) for 50% of all samples with the highest frequency in elderly people. Basing on the applied method for the determination of 25-OH-cholecalciferol concentrations a reference range for the Austrian population is suggested. The results show that low intakes of calcium and vitamin D lead to decreased status of these nutrients especially for adolescents, elderly, pregnant and lactating women, indicating the highest risk for the development of disorders of bone metabolism in these groups.

Adolescent↗
PubMed1984

Production of C-24- and C-23-oxidized metabolites of 1,25-dihydroxycholecalciferol by cultured kidney cells (LLC PK1) and their presence in kidney in vivo.

1,25-Dihydroxy[3H]cholecalciferol was converted into several more-polar metabolites by a cultured pig kidney cell line (LLC PK1). The production of metabolites was stimulated by pretreating the cells with unlabelled 1,25-dihydroxycholecalciferol. A similar profile of metabolites was observed on high-pressure-liquid-chromatographic analysis of an extract from the kidneys of rats dosed intravenously with 1,25-dihydroxy[3H]cholecalciferol. Among the metabolites detected were 1,24,25-trihydroxycholecalciferol, 1,25-dihydroxy-24-oxocholecalciferol, 1,23,25-trihydroxy-24-oxocholecalciferol and 1,25-dihydroxycholecalciferol-26,23-lactone. The results are in accord with data reported for intestinal 1,25-dihydroxycholecalciferol metabolism [Napoli, Pramanik, Royal, Reinhardt & Horst (1983) J. Biol. Chem. 258, 9100-9107]. These data indicate that C-23- and C-24-oxidation of 1,25-dihydroxycholecalciferol are phenomena common to calciferol target tissues, and that regulation of 1,25-dihydroxycholecalciferol homoeostasis is dependent on the rate of its metabolism in addition to the rate of its synthesis.

Animals↗
PubMed1982

Metabolism and molecular mechanism of action of vitamin D: 1981.

Cholecalciferol must be regarded as a pro-hormone rather than a vitamin, since it is normally produced in skin under the influence of ultraviolet light. Cholecalciferol must be metabolized in liver to 25-hydroxycholecalciferol and subsequently to 1,25-dihydroxycholecalciferol before it can act on intestine, bone and kidney to provide calcium and phosphorus for bone mineralization and neuromuscular activity. 1,25-Dihydroxycholecalciferol is metabolized in liver and intestine to a C-23-carboxylic acid that is inactive, 25-Hydroxycholecalciferol is metabolized to a variety of metabolic products, including 23S,25-dihydroxycholecalciferol, 23S,25R-25-hydroxycholecalciferol-26,23-lactone, 24R,25-dihydroxycholecalciferol and 25,26-dihydroxycholecalciferol. These metabolites are not involved in the known actions of vitamin D. 1,25-Dihydroxycholecalciferol localizes in the nuclei of target organs through a receptor mechanism. It is believed to initiate transcription of DNA that codes for calcium and phosphorus transport proteins, the nature of which is undetermined. Production of 1,25-dihydroxycholecalciferol is stimulated by low plasma calcium through parathyrin and by low plasma phosphorus. During pregnancy and lactation, 1,25-dihydroxycholecalciferol levels are greatly increased to meet calcium demands. However, vitamin D is not absolutely essential for reproduction. It is likely that some other hormone, possibly prolactin, functions at these periods to mobilize calcium. The clinical application of the vitamin D hormone and its analogues to the treatment of bone disease is presented to illustrate the application of basic science to medical practice. Evidence for each of these points is presented.

Adult↗
PubMed1977

Excretion of active metabolites of vitamin D in urine and bile of the adult rat.

1. One-year-old male rats were injected intravenously with 200 pmol of 25-hydroxy[26(27)-methyl-3H]cholecalciferol per 100 g body weight and the presence of this metabolite of vitamin D, as well as other metabolites, produced during the following 8 h was examined in serum, urine and bile. 2. The chromatography data indicated an excretion of 25-hydroxycholecalciferol both in bile and urine and, in urine, also of 1,25-dihydroxycholecalciferol. In bile, fractions of labelled substances were also obtained which, according to their elution positions, might represent cholecalciferol and conjugated metabolites. 3. The excretion of active metabolites of vitamin D in normal urine might be elevated in chronic renal failure and, in conjunction with a reduced synthesis, contribute to the occurrence of renal osteodystrophy.

Animals↗
PubMed1986

Evidence for extrarenal metabolism of 25-hydroxyvitamin D3 in man.

Metabolites of vitamin D3 were measured in the circulation of four patients on chronic haemodialysis (three of whom were surgically anephric) before and during daily ingestion of 40 000 i.u. of cholecalciferol. Circulating 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3] was measurable, but abnormally low before treatment; its circulating concentration rose in a substrate dependent manner when serum 25-hydroxyvitamin D3 (25-OHD3) increased, but the response was reduced when compared with the normal relationship. Serum 1,25-hydroxyvitamin D3 [1,25-(OH)2D3] and calcidiol lactone (25-OHD3-lactone) were consistently unmeasurable in sera from these patients before administration of cholecalciferol. However, when serum 25-OHD3 rose with treatment, 1,25-(OH)2D3 became detectable in the sera of three of the four patients and 25-OHD3-lactone could be measured in all of them. These data indicate that extrarenal sites of synthesis of 24,25-(OH)2D3, 25-OHD3-lactone and 1,25-(OH)2D3 exist in chronically dialysed patients but require large amounts of substrate to be significant.

Adult↗
PubMed2003

Effects of vitamin D supplementation on strength, physical function, and health perception in older, community-dwelling men.

OBJECTIVES: To study the effects of vitamin D supplementation in healthier populations of men. DESIGN: : Randomized, controlled trial. SETTING: General clinical research center. PARTICIPANTS: Sixty-five healthy, community-dwelling men (mean age+/-standard deviation=76+/-4, range 65-87). INTERVENTION: Cholecalciferol (1,000 IU/d) or placebo supplementation for 6 months; all received 500 mg supplemental calcium. MEASUREMENTS: Upper and lower extremity muscle strength and power, physical performance and activity, health perception, calcium and vitamin D intake, and biochemical assessment, including 25-hydroxyvitamin D (25OHD), parathyroid hormone (PTH), and ionized calcium levels. RESULTS: The levels of 25OHD increased and PTH decreased in the cholecalciferol group, whereas there were no significant changes in the control group (P<.001). Baseline 25OHD levels correlated with baseline single-leg stance time and physical activity score. Baseline PTH levels correlated with baseline 8-foot walk time and physical activity score. No significant difference in strength, power, physical performance, or health perception was found between groups. CONCLUSION: The 25OHD or PTH levels correlated with physical activity and physical performance in older, community-dwelling men with normal 25OHD status. Vitamin D supplementation increased 25OHD levels and decreased PTH levels but did not increase muscle strength or improve physical performance or health perception in this group of healthy, older men. Further investigations of the effects of vitamin D supplementation should focus on individuals with low levels of vitamin D.

25-Hydroxyvitamin D 2↗
PubMed1982

Effects of dietary phosphorus and calcium on the intestinal absorption of Ca in sheep.

1. Wether sheep were used, some of which were prepared with a Thiry-Vella loop of jejunum. The long-term use of these loops was ensured by regular perfusion with fresh nutrient solution. 2. The net calcium absorption rate from a Thirty-Vella loop of jejunum increased with increasing intraluminal Ca concentration and was increased by the addition of 1 alpha-hydroxy-cholecalciferol (3 micrograms/l) to the loop fluid. 3. When the diet of sheep was changed from one which was normal in Ca to a diet low in Ca there was an increase in the efficiency of net Ca absorption from the jejunal loop. This dietary change was accompanied by an increase in the circulating concentration of 1,25-dihydroxy-cholecalciferol (1,25(OH)2D3). 4. An intravenous infusion of the Ca chelating agent EDTA increased the efficiency of net Ca absorption from the jejunal loop. The use of 47Ca demonstrated that this reflected an increase in the true absorption rate of Ca. 5. Dietary phosphorus deficiency reduced the efficiency of intestinal Ca absorption and was associated with a reduction in the plasma concentration of 1,25(OH)2D3.

Animals↗
PubMed1996

Effectiveness of dietary 25- and 1-hydroxycholecalciferol in combating tibial dyschondroplasia in broiler chickens.

1. Three experiments were carried out to determine the effects of feeding diets containing different concentrations of cholecalciferol, 1 alpha-hydroxycholecalciferol (1-HCC), 25-hydroxycholecalciferol (25-HCC), 1,25-dihydroxycholecalciferol (1,25-DHCC) and ascorbic acid on the incidences and severities of tibial dyschondroplasia (TD) at 3 weeks of age in male broiler chicks. 2. In experiment 1, replacing 75 micrograms cholecalciferol/kg with the same weight of 25-HCC decreased significantly (P < 0.01) the incidence of TD from 65 to 10%. 3. In experiment 2, the incidence of TD in the control group was lower, but feeding amounts of 25-HCC up to 250 micrograms/kg had a linear effect on the incidence of TD that was significant at P = 0.06. There was no effect or interactions with dietary addition of 250 mg ascorbic acid/kg. Dietary addition of 5 micrograms 1-HCC/kg decreased TD incidence from 21 to 5%, though the effect was not significant (P > 0.1). 4. TD incidence in experiment 3 was too low to determine an effect of25-HCC or 1,25-DHCC on TD incidence, though in this, as in both other experiments, the severities of TD lesions were always lower with diets containing cholecalciferol metabolites. 5. Hypercalcaemia was not observed after feeding up to 250 micrograms 25-HCC/kg in either experiments 2 or 3. 6. It is concluded that 25-HCC may be an effective practical means of improving broiler leg health by alleviating the incidence and severity of TD.

Animals↗
PubMed1998

Metastatic mineralisation in brushtail possums (Trichosurus vulpecula) from Kawau Island.

AIMS: To describe the nature and incidence of metastatic mineralisation in brushtail possums (Trichosurus vulpecula) caught on Kawau Island. METHODS: Wild-caught possums were individually housed in captivity over a 24-month period and fed a cereal-based mash diet. Possums that became debilitated were examined post mortem for evidence of metastatic mineralisation of the heart, major blood vessels and kidneys. Serum and aortic segments were collected from affected animals and were analysed for mineral composition. Non-debilitated animals and possums that were experimentally poisoned with cholecalciferol were examined as a comparison. RESULTS: Fifteen of 42 possums (36%) captured on Kawau Island and housed in captivity were debilitated as a result of metastatic mineralisation of the walls of the aorta and/or of the kidney tubules, with four further possums having evidence of mineralisation when humanely killed. Phosphate and ammonium deposits were found in the aorta, and calcium deposits in the kidney tubules. Serum phosphorus and calcium levels were elevated in the debilitated animals. Similar lesions were found in only one of 288 possums captured from other North Island areas and housed in captivity over the same time period. CONCLUSION: Possums from Kawau Island appear to be more predisposed to metastatic mineralisation than possums from other areas of the North Island. The lesions observed in these possums were similar to those caused by cholecalciferol poisoning.

Journal Article↗
PubMed1984

Self-selection of a high calcium diet by vitamin D-deficient lactating rats increases food consumption and milk production.

Lactating and nonlactating rats, both deficient and replete in cholecalciferol, were allowed a free selection among three diets containing 0.47% Ca, 0.3% P (normal Ca, normal P diet); 2.0% Ca, 0.3% P (high Ca diet); and 0.47% Ca, 1.0% P (high P diet). An additional group of vitamin D-deficient lactating rats was fed only the normal Ca, normal P diet. Vitamin D-deficient rats showed a strong selection preference for the high Ca diet but avoided the high P diet, whereas cholecalciferol-replete rats consumed the normal Ca, normal P diet predominantly. Compared to the nonselecting rats, the selection of the high Ca diet by the lactating rats deficient in vitamin D resulted in an increase in plasma calcium levels, hypophosphatemia, a doubling of food consumption, a reduction in maternal body weight loss and a stimulation of milk production as indicated by pup growth. These results demonstrate that vitamin D-deficient rats select a high Ca diet and that the decrease in milk production found in vitamin D deficiency results from a decrease in food consumption and that this anorexia is at least partially dependent on the hypocalcemia normally occurring in vitamin D deficiency.

Animals↗
PubMed1989

Uptake of 75Se-selenite by brush border membrane vesicles from chick duodenum stimulated by vitamin D.

Brush border membrane vesicles were isolated from mucosal homogenates of duodena from normal, rachitic and vitamin D-treated rachitic chicks using a discontinuous sucrose gradient, and further purified by glycerol gradient centrifugation. In vitro uptake of 75Se-selenite by purified brush border membrane vesicles was studied using a rapid filtration technique. The time course of 75Se uptake was non-linear; rapid initial binding was followed by a gradual decrease in the rate of uptake until an equilibrium value was reached at 60-120 min. The initial binding at 36 s was not affected by selenite concentration in the incubation buffer, while the fractional rate of uptake between the 36 s and 2 min time periods was clearly lower with 1 mM Se than with 4-100 microM Se. 75Se uptake did not show any dependency on the external Na-gradient, nor could it be inhibited by other anions (arsenate, phosphate). Treatment of rachitic chicks either with cholecalciferol (500 Iu, 72 h) or with 1,25(OH)2-cholecalciferol (0.5 microgram given 16 h prior to isolation of the vesicles) significantly enhanced 75Se uptake. A threefold excess of mannitol in the outside buffer reduced 75Se uptake by vesicles from vitamin D-deficient and D-treated chicks 60% and 35% respectively, but had no effect on vesicles from vitamin D-treated chicks preloaded with 75Se. Neither saponin treatment nor excess cold selenite could release the label from the vesicles preloaded with 75Se. These data are compatible with the hypothesis that selenite easily crosses the brush border membrane into the intravesicular space and, once inside, is tightly bound by the membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Human mammary epithelial cells express CYP27B1 and are growth inhibited by 25-hydroxyvitamin D-3, the major circulating form of vitamin D-3.

1alpha,25-dihydroxycholecalciferol [1alpha,25(OH)2D3], the active form of cholecalciferol, is a negative growth regulator of breast cancer cells. CYP27B1 is a cytochrome P450-containing hydroxylase expressed in kidney and other tissues that generates 1alpha,25(OH)2D3 from an inactive vitamin D precursor 25-hydroxycholecalciferol [25(OH)D3]. In these studies, we tested the hypothesis that mammary cells express CYP27B1 and locally produce 1alpha,25(OH)2D3, which acts in an autocrine manner to regulate cell turnover. Using Western blot and quantitative real-time PCR, CYP27B1 mRNA and protein were detected in immortalized, nontumorigenic human mammary epithelial cell (HMEC) cultures. Furthermore, HMEC cultures were dose dependently growth inhibited by physiological concentrations of 25(OH)D3, suggesting that CYP27B1 converts this precursor cholecalciferol metabolite to 1alpha,25(OH)2D3, the ligand for the vitamin D receptor (VDR). In support of this suggestion, both 1alpha,25(OH)2D3 and 25(OH)D3 transactivated VDR in HMEC cultures, as measured by induction of a vitamin D responsive reporter gene and upregulation of CYP24, an endogenous VDR target gene. No induction of CYP24 by 25(OH)D3 was observed in mammary cells derived from CYP27B1 null mice. Similar results were observed in 2 independently derived immortalized HMEC lines as well as in primary cultures derived from human breast epithelium. These are the first studies to demonstrate that nontransformed human mammary cells express CYP27B1, that they are growth inhibited by physiologically relevant concentrations of 25(OH)D3, and that they provide a biological mechanism linking vitamin D status to breast cancer risk.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗