Jeffrey S. Mathieu

Vitamin D Deficiency in a Healthy Group of Mothers and Newborn Infants

Plasma 25-hydroxyvitamin D was measured in 40 healthy, mostly Black, mother-infant pairs. Although a majority of mothers received a daily prenatal multivitamin, vitamin D deficiency (<30 nmol/L), was found in 50% of mothers and 65% of their newborn infants, with a positive correlation between maternal and infant plasma 25-hydroxyvitamin D concentrations. Maternal vitamin D deficiency may represent an important risk factor for the development of rickets in children.

Widespread Vitamin D Deficiency in Urban Massachusetts Newborns and Their Mothers

OBJECTIVE: To determine vitamin D status and associated factors in a cohort of newly delivered infants and their mothers in Boston, Massachusetts. PATIENTS AND METHODS: Enrollment in this cross-sectional study took place from 2005 to 2007 in an urban Boston teaching hospital with 2500 births per year. A questionnaire and medical-record data were used to identify variables that are potentially associated with vitamin D deficiency (25-hydroxyvitamin D [25(OH)D] < 20 ng/mL). Infant and maternal blood was obtained by venipuncture within 72 hours of birth. The main outcome measure was infant and maternal 25(OH)D status, assessed by competitive protein binding. RESULTS: We enrolled 459 healthy mother/infant pairs. After subsequent exclusions, analyses were performed on 376 newborns and 433 women. The median infant 25(OH)D level was 17.2 ng/mL (95% confidence interval [CI]: 16.0–18.8; range: <5.0 to 60.8 ng/mL). The median maternal 25(OH)D level was 24.8 ng/mL (95% CI: 23.2–25.8; range: <5.0 to 79.2 ng/mL). Overall, 58.0% of the infants and 35.8% of the mothers were vitamin D deficient (25[OH]D < 20 ng/mL); 38.0% of the infants and 23.1% of the mothers were severely deficient (25[OH]D < 15 ng/mL). Risk factors for infant vitamin D deficiency included maternal deficiency (adjusted odds ratio [aOR]: 5.28 [95% CI: 2.90–9.62]), winter birth (aOR: 3.86 [95% CI: 1.74–8.55]), black race (aOR: 3.36 [95% CI: 1.37–8.25]), and a maternal BMI of ≥35 (aOR: 2.78 [95% CI: 1.18–6.55]). Maternal prenatal-vitamin use throughout the second and third trimesters was protective against infant deficiency (aOR: 0.30 [95% CI: 0.16–0.56]). Similarly, prenatal-vitamin use of ≥5 times per week in the third trimester was protective for mothers (aOR: 0.37 [95% CI: 0.20–0.69]). Despite this, >30% of the women who took prenatal vitamins were still vitamin D deficient at the time of birth. CONCLUSIONS: A high proportion of infants and their mothers in New England were vitamin D deficient. Prenatal vitamins may not contain enough vitamin D to ensure replete status at the time of birth.

Evaluation of C-2-substituted 19-nor-1α,25-dihydroxyvitamin D3 analogs as therapeutic agents for prostate cancer

1alpha,25-Dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) is known to inhibit the proliferation and invasiveness of prostate cancer cells. However, 1alpha,25(OH)(2)D(3) can cause hypercalcemia and is not suitable as a therapeutic agent. 19-Nor-vitamin D derivatives are known to be less calcemic when administered systemically. In order to develop more potent anti-cancer agents with less calcemic side effect, we therefore utilized (3)H-thymidine incorporation as an index for cell proliferation and examined the antiproliferative activities of nine C-2-substituted 19-nor-1alpha,25(OH)(2)D(3) analogs in the immortalized PZ-HPV-7 normal prostate cell line. Among the nine analogs we observed that the substitution with 2alpha- or 2beta-hydroxypropyl group produced two analogs having antiproliferative potency that is approximately 500- to 1000-fold higher than 1alpha,25(OH)(2)D(3). The (3)H-thymidine incorporation data were supported by the cell counting data after cells were treated with 1alpha,25(OH)(2)D(3), 19-nor-2alpha-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) or 19-nor-2beta-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) for 7 days. 19-Nor-2alpha-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) and 19-nor-2beta-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) were also shown to be about 10-fold more active than 1alpha,25(OH)(2)D(3) in cell invasion studies using prostate cancer cells. In conclusion, a substitution at the C-2 position of 19-nor-1alpha,25(OH)(2)D(3) molecule with a hydroxypropyl group greatly increased the antiproliferative and anti-invasion potencies. Thus, these two analogs could be developed to be effective therapeutic agents for treating early and late stages of prostate cancer.

An evaluation of the biologic activity and vitamin D receptor binding affinity of the photoisomers of vitamin D3 and previtamin D3.

Skin is in the site of previtamin D3 and vitamin D3 synthesis and their isomerization in response to ultraviolet irradiation. At present, little is known about the function of the photoisomers of previtamin D3 and the vitamin D3 in skin cells. In this study we investigated the antiproliferative activity of the major photoisomers and their metabolites in the cultured human keratinocytes by determining their influence on 3H-thymidine incorporation into DNA. Our results demonstrated at both 10(-8) and 10(-6) M in a dose-dependent manner. Lumisterol, tachysterol3, 5,6-trans-vitamin D3, and 25-hydroxy-5,6-trans-vitamin D3 only induced significant inhibition at 10(-6) M. 25-Hydroxytachysterol3 was approximately 10- to 100-fold more active than tachysterol3. 7-Dehydrocholesterol was not active even at 10(-6) M. The dissociation constants of vitamin D receptor (VDR) for 25-hydroxytachysterol3, 25-hydroxy-5,6-trans-vitamin D3, and 5,6-trans-vitamin D3 were 22, 58, and 560 nM, respectively. The dissociation constants for 7-dehydrocholesterol, tachysterol, and lumisterol were greater than 20 microM. In conclusion, vitamin D3, its photoisomers and the photoisomers of previtamin D3 have antiproliferative activity in cultured human keratinocytes. However, the antiproliferative activity did not correlate with their binding affinity for VDR. The results suggest that some of the photoproducts may be metabolized to their 25-hydroxylated and 1 alpha,25-dihydroxylated counterparts before acting on VDR. Alternatively, a different receptor may recognize these photoproducts or another mechanism may be involved in modulating the antiproliferative activity of the photoisomers examined.

T1150 Efficacy of Two Different Weekly Doses of Vitamin D (400 Iu and 50,000 Iu) in Patients with Crohn's Disease in Improving Vitamin D Nutritional Status

Background: Vitamin D deficiency is prevalent among patients with Crohns disease (CD). Factors predisposing to hypovitaminosis D in these patients may include lack of adequate vitamin D intake or supplementation and malabsorption. Since these factors have been poorly described in patients with CD, the aims of this study were to assess baseline serum vitamin D status and the efficacy of a standard pharmacologic dose of vitamin D in improving serum 25(OH)D levels.Methods: Consecutive adult patients with CD presenting for routine office visits to Boston Medical Center participated in the study from April 2007 to November 2007. Baseline serum 25(OH)D levels were measured by HPLC in 21 consecutive patients after which patients were randomized to receive either 50,000 IU (n = 14) or 400 IU (n = 7) of vitamin D2 q week for seven weeks. At the end of the study, changes in serum 25(OH)D from baseline were compared. As secondary endpoints, changes from baseline in serum calcium, hematocrit, ESR, CRP were measured. In addition, changes in serum levels of 12 cytokines (GMCSF, IFN-gamma, IL-10, IL-1beta, IL-s, IL-4, IL-5, IL-6, IL-8, MCP-1, MIP-1alpha, TNF-alpha) were evaluated by using multi-analyte profiling beads (Luminex, Toronto, ON). Results: Baseline serum levels of 25(OH)D were not significantly different between treatment arms (21.3 vs. 26.1 ng/ml). Both treatment arms significantly increased serum 25(OH)D levels over baseline. Those patients receiving 50,000 IU of vitamin D weekly had a mean increase of 25(OH)D of 61% (26.1 to 37 ng/ml, p=0.007) while those receiving 400 IU of vitamin D weekly had a mean increase of 25(OH)of 128% (21.3 to 41.6 ng/ml, p=0.035). There was no significant difference in end serum levels of 25(OH)D between the treatment arms (41.6 vs. 37.8 ng/ml). Neither a significant increase in serum 25(OH)D levels nor randomization to the 50,000 IU per week arm of the study had an effect any laboratory markers of disease activity (ESR, CRP, Hct) nor on serum cytokine levels. One patient in the high dose group discontinued the study medication after 4 doses secondary to increased diarrhea. Conclusions: 50,000 IU of vitamin D given once a week for 7 weeks was no more effective than 400 IU of vitamin D given once a week for 7 weeks in raising serum 25(OH)D levels. Hence, other variables that affect serum vitamin D levels such as sun exposure due to seasonal variation over the course of the study may be responsible for the significant increase in serum 25(OH)D in each group. The lack of difference in serum 25(OH)D levels between the two groups may be due to compromised absorption secondary to their Crohns disease.

An Evaluation of the Biologic Activity and Vitamin D Receptor Binding Affinity of the Photoisomers of Vitamin D3, Previtamin D3 and Their Hydroxylated Derivatives

During exposure to sunlight, the UVB portion of the solar spectrum (295-315 nm) photolyzes 7-dehydrocholesterol (7-DHC) in epidermis to previtamin D3. Previtamin D3 then thermoisomerizes to vitamin D3 (1). Vitamin D3 is hydroxylated in the liver at C-25 to form 25-hydroxyvitamin D3 [25(OH)D3], followed by hydroxylation at the C-lin kidneys to form 1,25dihydroxyvitamin D3 [1,25(OH)2D3], the active form of vitamin D. However, further exposure to sunlight can photoisomerize previtamin D3 and vitamin D3 to a variety of photoproducts, including 5,6-trans-vitamin D3, tachysterol, and lumisterol (2,3). Since they are produced locally in the skin, their concentration could be very high. Among these photoproducts, tachysterol and 5,6-trans-vitamin D3 have a pseudo-1-a-hydroxyl structure due to the 180 degree rotation of the 3-hydroxyl group during the isomerization (Figure 1).