A B S T R A C T The influence of the serum binding protein (DBP) for vitamin D and its metabolites on the concentration of its main ligands, 25-hydroxyvitamin D3 (25-OHD3) and 1,25-dihydroxyvitamin D3 (1,25-[OHh2D3) was studied. The concentration of both 1,25-(OH)2D3 and DBP in normal female subjects (45±14 ng/liter and 333±58 mg/liter, mean+SD, respectively; n = 58) increased during the intake of estro-progestogens (69±27 ng/liter and 488±90 mg/liter, respectively; n = 29), whereas the 25-OHD3 concentration remained unchanged. A positive correlation was found between the concentrations of 1,25-(OH)2D3 and DBP in these women.At the end of pregnancy, the total concentrations of 1,25-(OH)2D3 (97±26 ng/liter, n = 40) and DBP (616 ±84 mg/liter) are both significantly higher than in nonpregnant females and paired cord serum samples (48±11 ng/liter and 266±41 mg/liter, respectively). A marked seasonal variation of 25-OHD3 was observed in pregnant females and their infants, whereas in the same samples the concentrations of both DBP and 1,25-(OH)2D3 remained constant throughout the year.The free 1,25-(OH)2D3 index, calculated as the molar ratio ofthis steroid and DBP, remains normal in women taking estro-progestogens, however, and this might explain their normal intestinal calcium absorption despite a high total 1,25-(OH)2D3 concentration. In pregnancy the free 1,25-(OH)2D3 index remains normal up to 35 wk of gestation, but during the last weeks of Part of this work was presented at

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The human serum vitamin D-binding protein (DBP) has many physiologically important functions, ranging from transporting vitamin D3 metabolites, binding and sequestering globular actin and binding fatty acids to functioning in the immune system. Here we report the 2.3 A crystal structure of DBP in complex with 25-hydroxyvitamin D3, a vitamin D3 metabolite, which reveals the vitamin D-binding site in the N-terminal part of domain I. To more explicitly explore this, we also studied the structure of DBP in complex with a vitamin D3 analog. Comparisons with the structure of human serum albumin, another family member, reveal a similar topology but also significant differences in overall, as well as local, folding. These observed structural differences explain the unique vitamin D3-binding property of DBP.

The concentration of the vitamin D-binding protein was measured in human serum by single radial immunodiffusion. Normal serum concentrations were slightly higher in normal women than in normal men. No race-related difference was found between white people from Belgium and black people from Zaire. Lower concentrations were found in cord serum and in patients with cirrhosis of the liver. Increased serum levels were observed during pregnancy or during the intake of estro-progestogens. The serum level of the vitamin D-binding protein was not altered in various diseases of calcium metabolism (primary osteoporosis, primary and secondary hyperparathyroidism, rickets, osteomalacia or vitamin D intoxication). No correlation was found between serum levels of 25-hydroxy vitamin D and those of its binding protein. From these data the following conclusions can be drawn: 1) The serum concentration of the vitamin D-binding protein (about 6.10(-6)M) largely exceeds the normal serum concentration of 25-hydroxy vitamin D (about 4.10(-8)M), so that this protein is normally for less than 1% saturated, 2) Normal serum levels of the vitamin D-binding protein were observed in several diseases of calcium metabolism, and 3) The free concentration of 25-hydroxyvitamin D is not regulated at a constant level.

Serum calcium, phosphorus, albumin, total protein, 25-hydroxyvitamin D (25OHD) and the vitamin D-binding protein (DBP) were measured in 30 cord sera and in 30 sera obtained simultaneously from their respective mothers. The maternal serum concentration of 25OHD (14.0 +/- 6.9 microgram/l, mean +/- SD) and of DBP (574 +/- 72 mg/l) were significantly higher than the respective cord serum concentration (8.0 +/- 4.4 microgram/l and 268 +/- 39 mg/l). The calculated concentration of "free 25OHD," however, was slightly but significantly higher in cord serum (0.44 +/- 0.24 ng/l) than in maternal serum (0.34 +/- 0.18 ng/l). Serum calcium and phoshporus were lower in maternal than in cord serum. A highly significant positive correlation was found between maternal and cord serum concentration of DBP (r = 0.59), total 25OHD (r = 0.79), "free 25OHD" (r = 0.86) and phosphorus (r = 0.73). These data indicate that the concentration of DBP is important for the evaluation of the placental transfer of 25OHD. Indeed, the concentration of "free 25OHD" is slightly higher in cord serum than in maternal serum, despite the maternal-to-fetal gradient of total 25OHD. The low fetal concentration of DBP is also unfavorable for the fetal storage of 25OHD during intrauterine life.