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Biomedical subjects

Michael F Holick

Publications and source records attributed to Michael F Holick.

67 records · Page 4Linked to original sources
PubMed2002

25-Hydroxyvitamin D-1alpha-hydroxylase activity is diminished in human prostate cancer cells and is enhanced by gene transfer.

The hormone 1alpha,25-dihydroxyvitamin D (1alpha,25(OH)(2)D) inhibits growth and induces differentiation of prostate cells. The enzyme responsible for 1alpha,25(OH)(2)D synthesis, 25-hydroxyvitamin D (25(OH)D)-1alpha-hydroxylase (1alpha-OHase), has been demonstrated in human prostate cells. We compared the levels of 1alpha-OHase activity in prostate cancer cell lines, LNCaP, DU145 and PC-3 and in primary cultures of normal, cancerous and benign prostatic hyperplasia (BPH) prostate cells. We observed a marked decrease in 1alpha-OHase activity in prostate cancer cells, including an undetectable level of activity in LNCaP cells. Transient or stable transfection of 1alpha-OHase cDNA into LNCaP cells increased 1alpha-OHase activity from undetectable to 4.95pmole/mg+/-0.69pmole/mg and 5.8pmole/mg+/-0.7pmole/mg protein per hour, respectively. In response to 25(OH)D, the prohormone of 1alpha,25(OH)(2)D, the transfected LNCaP cells showed a significant inhibition of 3H-thymidine incorporation (37%+/-6% and 56%+/-4% at 10(-8)M for transiently and stably transfected cells, respectively). These findings support an important autocrine role for 1alpha,25(OH)(2)D in the prostate and suggest that the re-introduction of the 1alpha-OHase gene to prostate cancer cells, in conjunction with the systemic administration of 25(OH)D, constitutes an endocrine form of gene therapy that may be less toxic than the systemic administration of 1alpha,25(OH)(2)D.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2002

Bone mineral density assessment: comparison of dual-energy X-ray absorptiometry measurements at the calcaneus, spine, and hip.

It is widely accepted that bone mineral density (BMD) measurements obtained by dual-energy X-ray absorptiometry (DXA) at the spine, hip, and calcaneus predict fracture risk. Few published studies to date have examined the relationship between pDXA measurements at the calcaneus to those at the hip and spine. It has been demonstrated that T-score-based criteria cannot be universally applied to all skeletal sites and measurement technologies. Our goal was to define the calcaneal T-score threshold equivalent to low bone mass at the hip or spine. A total of 119 female patients between the ages of 33 and 76 yr of age were recruited at Boston University Medical Center for bone densitometry screening. Bone density measurements were obtained at the calcaneus using the portable Norland Apollo Densitometer (Norland Medical Systems, Fort Atkinson, WI) and at the hip and spine using the Norland Eclipse densitometer. By defining a pDXA T-score < or =-1 as a positive test and DXA scores < or =-1 as the presence of low bone mass, we obtained a specificity of 100% and a sensitivity of 73% (positive predictive value 100% and negative predictive value 80%) in detecting low bone mass at the femoral neck in women over age 65 yr. In women between 40 and 65 yr of age, we obtained a sensitivity of 50% and a specificity of 93% (positive predictive value 93% and negative predictive value 50%) in detecting low bone mass at the femoral neck. In women less than 40 yr of age, we obtained a sensitivity of 13% and a specificity of 100% (positive predictive value 100% and negative predictive value 75%) in detecting low bone mass at the femoral neck. From receiver operating characteristic curves, a calcaneal T-score < or =0.0 detects those with a T-score < or =-1 at the femoral neck and lumbar spine with 100% and 85% sensitivity, respectively. Peripheral DXA of the calcaneus is a sensitive and specific test to diagnose low bone mass in women over 65 yr of age. In women under 65 yr of age, this modality, though not as sensitive, is specific in detecting low bone mass. We conclude that a pDXA calcaneal T-score < or =0 is highly sensitive in predicting osteopenia and osteoporosis at the femoral neck and lumbar spine.

Absorptiometry, Photon↗
PubMed2002

Fat soluble vitamins in blood and tissues of free-ranging and captive rhinoceros.

Several disease syndromes in captive rhinoceroses have been linked to low vitamin status. Blood samples from captive and free-ranging black (Diceros bicornis) and white rhinoceros (Ceratotherium simum) and tissue samples of captive individuals from four rhinoceros species were analysed for vitamins A and E. Circulating vitamin A levels measured as retinol for free-ranging versus captive black and white rhinoceros were 0.04 (+/- 0.03 SD) vs. 0.08 (+/- 0.08) and 0.07 (+/- 0.04) vs. 0.06 (+/- 0.02) microgram/ml, respectively. Circulating vitamin E levels measured as alpha-tocopherol were 0.58 (+/- 0.30) vs. 0.84 (+/- 0.96) and 0.62 (+/- 0.48) vs. 0.77 (+/- 0.32) microgram/ml, respectively. In contrast to earlier findings, there was no significant difference in vitamin E concentration between captive and free-ranging black rhinoceros. When the samples of captive black rhinoceros were grouped into those taken before 1990 and after 1990, however, those collected before 1990 had significantly lower (P < 0.001) vitamin E levels (0.46 +/- 0.83 microgram/ml) and those collected in 1990 or later significantly higher (P < 0.001) vitamin E levels (1.03 +/- 1.04 micrograms/ml) than the captive population as a whole. This is probably due to increased dietary supplementation. There were significant differences in circulating vitamin concentrations in black rhinoceroses from different regions in the wild. Serum 25-hydroxy (OH) vitamin D3 averaged 55.7 ng/ml in free-ranging rhinoceroses; no carotenoids were detected in any blood samples. Captive black and white rhinoceroses appear to be adequately supplemented in vitamin A and E. Captive Indian rhinoceroses (Rhinoceros unicornis) had significantly lower vitamin A concentrations in blood (P < 0.001) and higher vitamin A concentrations in liver tissue samples (P < 0.001) than other rhinoceros species. Equine requirements are not recommended as a model for rhinoceros vitamin requirements.

Adipose Tissue↗
PubMedDate not supplied

Do panther chameleons bask to regulate endogenous vitamin D3 production?

Basking by ectothermic vertebrates is thought to have evolved for thermoregulation. However, another beneficial effect of sunlight exposure, specifically the ultraviolet B (UV-B) component, includes endogenous production of vitamin D(3). In the laboratory, panther chameleons exhibited a positive phototaxis to greater visible, ultraviolet A (UV-A) and UV-B light. However, with equivalent high irradiances of UV-A or UV-B, their response to UV-B was significantly greater than it was to UV-A. Exposure of in vitro skin patches of panther chameleons to high UV-B (90 microW/cm(2)) for 1 h significantly enhanced vitamin D(3) concentration. Voluntary exposure to higher UV-B irradiance (70 vs. 1 microW/cm(2)) resulted in greater circulating 25-hydroxyvitamin D(3) in female panther chameleons (604 vs. 92 ng/mL). Depending on dietary intake of vitamin D(3), chameleons adjusted their exposure time to UV-B irradiation as if regulating their endogenous production of this vital hormone. When dietary intake was low (1-3 IU/g), they exposed themselves to significantly more UV-producing light; when intake was high (9-129 IU/g), they exposed themselves to less. Vitamin D(3) photoregulation seems to be an important additional component of the function of basking.

Animals↗
PubMedDate not supplied

Vitamin D for health and in chronic kidney disease.

Vitamin D is taken for granted and is not appreciated for its importance in overall health and well-being. Vitamin D, known as the sunshine vitamin, is appreciated as being important for the prevention of rickets in children. It is now recognized that vitamin D is important for not only the growing skeleton, but for the maintenance of a healthy musculoskeletal system throughout life. Vitamin D deficiency in adults precipitates and exacerbates osteoporosis and causes the painful bone disease osteomalacia. The revelation that vitamin D is biologically inactive and requires sequential hydroxylations in the liver and kidney to form 1,25-dihydroxyvitamin D helps explain why patients with renal failure are often resistant to vitamin D and suffer from secondary hyperparathyroidism and renal osteodystrophy. In addition to its role in maintaining calcium and phosphorus homeostasis, vitamin D is now being recognized as important for maintaining maximum muscle strength and for the prevention of many chronic diseases, including type I diabetes, multiple sclerosis, rheumatoid arthritis, hypertension, cardiovascular heart disease, and many common cancers. Vitamin D status is best determined by the measurement of circulating levels of 25-hydroxyvitamin D. Vigilance for maintaining a 25-hydroxyvitamin D level of at least 20 ng/ml and preferably 30-50 ng/ml has important benefits for both healthy children and adults, as well as children and adults suffering from chronic kidney disease.

Autoimmune Diseases↗
PubMedDate not supplied

Comparisons of estimated economic burdens due to insufficient solar ultraviolet irradiance and vitamin D and excess solar UV irradiance for the United States.

Vitamin D sufficiency is required for optimal health, and solar ultraviolet B (UVB) irradiance is an important source of vitamin D. UVB and/or vitamin D have been found in observational studies to be associated with reduced risk for over a dozen forms of cancer, multiple sclerosis, osteoporotic fractures, and several other diseases. On the other hand, excess UV irradiance is associated with adverse health outcomes such as cataracts, melanoma, and nonmelanoma skin cancer. Ecologic analyses are used to estimate the fraction of cancer mortality, multiple sclerosis prevalence, and cataract formation that can be prevented or delayed. Estimates from the literature are used for other diseases attributed to excess UV irradiation, additional cancer estimates, and osteoporotic fractures. These results are used to estimate the economic burdens of insufficient UVB irradiation and vitamin D insufficiency as well as excess UV irradiation in the United States for these diseases and conditions. We estimate that 50,000-63,000 individuals in the United States and 19,000-25,000 in the UK die prematurely from cancer annually due to insufficient vitamin D. The U.S. economic burden due to vitamin D insufficiency from inadequate exposure to solar UVB irradiance, diet, and supplements was estimated at $40-56 billion in 2004, whereas the economic burden for excess UV irradiance was estimated at $6-7 billion. These results suggest that increased vitamin D through UVB irradiance, fortification of food, and supplementation could reduce the health care burden in the United States, UK, and elsewhere. Further research is required to confirm these estimates.

Cataract↗
PubMedDate not supplied

Vitamin D metabolism in human prostate cells: implications for prostate cancer chemoprevention by vitamin D.

BACKGROUND: Prostate cells can produce 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) from 25-hydroxyvitamin D3 (25(OH)D3) to regulate their own growth. Here, the questions of whether prostate cells express vitamin D-25-hydroxylase (25-OHase) and can convert vitamin D3 to 1alpha,25(OH)2D3 were investigated. MATERIALS AND METHODS: Protein and receptor binding assays were used to determine 25(OH)D3 and 1alpha,25(OH)2D3, respectively. Measurements of proliferation by 3H-thymidine incorporation, and 1alpha,25(OH)2D-responsive gene expression by real-time qPCR and by Western blot were used as functional assays for the presence of 25-OHase activity. RESULTS: Prostate cells metabolized vitamin D3 to 1alpha,25(OH)2D3. Vitamin D3 up-regulated 25(OH)D-24R-hydroxylase and IGFBP3, two 1alpha,25(OH)2D-responsive genes, in prostate cells. CYP2R1 was the major form of 25-OHase expressed in normal and cancerous prostate cells as determined by qPCR. CONCLUSION: The autocrine synthesis of 1alpha,25(OH)2D3 from vitamin D3 suggests that maintaining adequate levels of serum vitamin D could be a safe and effective chemo-preventive measure to decrease the risk of prostate cancer.

Calcifediol↗
PubMedDate not supplied

Analysis of 25-hydroxyvitamin D3-1alpha-hydroxylase in normal and malignant breast tissue.

BACKGROUND: The presence of extra-renal 25-hydroxyvitamin D3 [25(OH)D3]-1alpha-hydroxylase (1alpha-OHase) has been reported in several cell types including prostate and colon cancer cells. Additionally, alterations in the local production of 1alpha,25-dihydroxyvitamin D [1alpha,25(OH)2D3] have been implicated in the tumorigenesis of these malignancies. The aim of this study was to analyze whether normal breast tissue or breast cancer cells expressed 1alpha-OHase and to evaluate whether breast tissue possessed the capacity to produce 1alpha,25(OH)2D3 from 25(OH)D3. MATERIALS AND METHODS: Total RNA was extracted from normal breast tissue (n = 11), breast carcinomas (n = 12) and cultured MCF-7 breast cancer cells for real-time (LightCycler using specific hybridization probes) and conventional PCR analysis. RESULTS: mRNA for 1alpha-OHase was detected in breast cancer tissue and in MCF-7 breast cancer cells. Interestingly, the mRNA levels for 1alpha-OHase were significantly increased in breast cancer compared to normal breast tissue. When the MCF-7 cells were treated with 1alpha,25(OH)2D3, cell proliferation was inhibited in a dose-dependent manner. Incubation of the MCF-7 cells with [3H]-25(OH)D3 resulted in its conversion to [3H]-1,25(OH)2D3. The 1alpha-OHase activity in the MCF-7 cells was blocked by a specific cytochrome P450 inhibitor, clotrimazole. CONCLUSION: The data suggest that at least breast cancer cells expressed 1alpha-OHase mRNA and, therefore, might have the ability to synthesize 1alpha,25(OH)2D3 within the cells. The local production of 1alpha,25(OH)2D3 might play an important role in regulating the proliferation and differentiation of breast cells. We hypothesize that alterations in the local production of 1alpha,25(OH)2D3 may be involved in the tumorigenesis of breast cancer. Additionally, breast cancer may be a target for treatment with precursors of biologically-active vitamin D analogs.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗