Dihydroxyvitamine

Dihydroxyvitamin (283) is the endogenous ligand for the vitamin receptor (VDR). It modulates genomic function in a tissue and developmentaHy specific manner and affects ceU proliferation, differentiation, and mineral homeostasis (74). Vitamin mobilizes calcium from the bone to maintain plasma Ca " levels. Vitamin and VDR are present in the CNS where they may play a role in regulating Ca " homeostasis. Vitamin D has potent immunomodulatory activity in vivo. 

Fig. 9. Human disease states in which vitamin D has been impHcated. D3 = vitamin D DHD = la, 25 — dihydroxyvitamin D ...

FIGURE 18.37 (a) Vitamin D3 (cholecalciferol) is produced in the skin by the action of sunlight on 7-dehydrocholesterol. The successive action of mixed-function oxidases in the liver and kidney produces 1,25-dihydroxyvitamin D3, the active form of vitamin D. 

Chemical Name 9,10-Secocholesta-5,7,10(19)-triene-1,3,25-triol Common Name 10(,25-Dihydroxycholecalciferol 10(,25-dihydroxyvitamin D3 Structural Formula ... 

PTH has a dual effect on bone cells, depending on the temporal mode of administration given intermittently, PTH stimulates osteoblast activity and leads to substantial increases in bone density. In contrast, when given (or secreted) continuously, PTH stimulates osteoclast-mediated bone resorption and suppresses osteoblast activity. Further to its direct effects on bone cells, PTH also enhances renal calcium re-absorption and phosphate clearance, as well as renal synthesis of 1,25-dihydroxy vitamin D. Both PTH and 1,25-dihydroxyvitamin D act synergistically on bone to increase serum calcium levels and are closely involved in the regulation of the calcium/phosphate balance. The anabolic effects of PTH on osteoblasts are probably both direct and indirect via growth factors such as IGF-1 and TGF 3. The multiple signal transduction... 

LiEL Y, SHANY s, SMIRNOFF p and SCHWARTZ B (1999) Estrogen increases 1,25-dihydroxyvitamin D receptors expression and bioresponse in the rat duodenal mucosa. Endocrinol 140, 280-85. 

Amir, H. et ah. Lycopene and 1,25-dihydroxyvitamin D3 cooperate in the inhibition of cell cycle progression and induction of differentiation in HL-60 leukemic cells, Nutr. Cancer, 33, 105, 1999. 

Other vitamin D analogs available in the United States include paricalcitol (19-nor-l,25-dihydroxyvitamin D2, Zemplar by Abbott Laboratories, North Chicago, IL) and doxercalciferol (1 -a-hydroxyvitamin D2, Hectoral by Bone Care International, Middleton, WI). Alfacalcidiol (1-a-hydroxyvitamin D3) is only available outside the United States. Paricalcitol has less effect on vitamin D receptors in the intestines, decreasing the effects on... 

Diet Increased risk associated with high-meat and high-fat diets. Decreased intake of 1, 25-dihydroxyvitamin D, vitamin E, lycopene, and /Tcarotene increases risk. 

Around 99% of calcium is contained in the bones, whereas the other 1% resides in the extracellular fluid. Of this extracellular calcium, approximately 40% is bound to albumin, and the remainder is in the ionized, physiologically active form. Normal calcium levels are maintained by three primary factors parathyroid hormone, 1,25-dihydroxyvitamin D, and calcitonin. Parathyroid hormone increases renal tubular calcium resorption and promotes bone resorption. The active form of vitamin D, 1,25-dihydroxyvitamin D, regulates absorption of calcium from the GI tract. Calcitonin serves as an inhibitory factor by suppressing osteoclast activity and stimulating calcium deposition into the bones. 

A third and less common mechanism is production of 1,25-dihydroxyvitamin D by tumor cells (usually lymphoma), which increases GI absorption of calcium and enhances osteoclastic bone resorption. 

NS (general population) Other Negative correlation between blood lead and serum 1,25-dihydroxyvitamin D in children 12-120 Mahaffey et al. 1982 Rosen et al. 1980... 

Effects on Vitamin D Metabolism. Lead interferes with the conversion of vitamin D to its hormonal form, 1,25-dihydroxyvitamin D. This conversion takes place via hydroxylation to 25-hydroxyvitamin D in the liver followed by 1-hydroxylation in the mitochondria of the renal tubule by a complex cytochrome P-450 system (Mahaffey et al. 1982 Rosen and Chesney 1983). Evidence for this effect comes primarily from studies of children with high lead exposure. 

The possible mechanism kidney-induced hypertension is discussed in Section 2.4.2, Mechanisms of Toxicity. Lead appears to affect vitamin D metabolism in renal tubule cells, such that circulating levels of the vitamin D hormone, 1,25-dihydroxyvitamin D, are reduced. This effect is discussed later in this section under Other Systemic Effects. 

Reduction in the serum 1,25-dihydroxyvitamin D concentration has been reported as an indicator of increased lead absorption or lead levels in the blood (Rosen et al. 1980). Lead inhibits the formation of this active metabolite of vitamin D, which occurs in bone mineral metabolism (EPA 1986a Landrigan 1989). Children with PbB concentrations of 12-120 pg/dL lead showed decreased serum 1,25-dihydroxyvitamin D concentrations comparable to those found in patients with hypoparathyroidism, uremia, and metabolic bone disease (Mahaffey et al. 1982 Rosen et al. 1980). This biomarker is clearly not specific for lead exposure and several diseases can influence this measurement. 

Children with elevated PbB (12-120 pg/dL) were found to have significantly lower serum concentrations of the vitamin D metabolite 1,25-dihydroxy vitamin D compared with age-matched controls (p<0.001), and showed a negative correlation of serum 1,25-dihydroxyvitamin D with lead over the range of blood lead levels measured (Mahaffey et al. 1982 Rosen et al. 1980). 

Long GJ, Rosen JF. 1994. Lead perturbs 1,25 dihydroxyvitamin D3 modulation of intracellular calcium metabolism in clonal rat osteoblastic (ros 17/2.8) cells. Life Sci 54(19) 1395-1402. 

Rosen JF, Chesney RW, Hamstra AJ, et al. 1981. Reduction in 1,25-dihydroxyvitamin D in children with increased lead absorption. In Brown SS, Davis DS, eds. Organ-directed toxicity Chemical indices and mechanisms. New York, NY Pergamon Press, 91-95. 

Liu, Y., Chang, R.L., Cui, X.X., Newmark, H.L. and Conney, A.H. 1997. Synergistic effects of curcumin on all-trans retinoic acid- and 1 alpha,25-dihydroxyvitamin D3-induced differentiation in human promyelocytic leukemia HL-60 cells. Oncol Res 9 19-29. 

K. E., Fisher, J. M., Paine, M. F., Lown, K. S., Watkins, P. B., Expression of enzymatically active CYP3A4 by Caco-2 cells grown on extracellular matrix-coated permeable supports in the presence of 1-alpha,25-dihydroxyvitamin D3, Mol. Pharmacol. 1997, 53, 741-754. 

Vitamin D receptor (VDR) 1,25 dihydroxyvitamin-D3 Vitamin D response in patients affected with rickets (96) Susceptibility to osteoporosis (97) and autosomal dominant rickets disease (96)... 

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