Human Placental Production of lα,25-Dihydroxyvitamin D3: Biochemical Characterization and Production in Normal Subjects and Patients with Pseudohypoparathyroidism*

Abstract

Biochemical characterization of placental 25-hydroxyvitamin D3-1 alpha-hydroxylase was performed in placentas from eight normal women. Production of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] was linear with time; the mean production rate was 282 +/- 74 (+/- SE) pg/mg protein X h. Only the fetally derived trophoblasts had significant 1 alpha-hydroxylase activity, and this was located solely in mitochondria. Kinetic analysis of 1 alpha-hydroxylation in isolated mitochondria from normal placentas disclosed a Km for 25-hydroxyvitamin D3 of 0.57 microM. To assess whether placentas from women with disorders of vitamin D metabolism could also produce 1,25-(OH)2D3, we measured the placental production rates of 1,25-(OH)2D3 in three women with PTH-resistant hypoparathyroidism (pseudohypoparathyroidism) during four separate pregnancies. Their mean production rate of 1,25-(OH)2D3 was 353 +/- 184 pg/mg protein X h, a value not significantly different from that of normal placentas. Therefore, placental production of 1,25-(OH)2D3 may provide a significant contribution to the circulating concentration of 1,25-(OH)2D3. In women with PTH-resistant hypoparathyroidism, in whom the renal capacity to synthesize 1,25-(OH)2D3 is impaired, placental production of 1,25-(OH)2D3 is not compromised.

Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone

“…Vitamin D receptors within renal proximal convoluted tubule cells are involved in an autocrine negative feedback loop, whereby increased levels of 1,25-(OH) 2 D 3 will down-regulate 1,25-(OH) 2 D 3 production (Takeyama et al 1997). Other known important extra-renal sites of 1,25-(OH) 2 D 3 production are the placenta and granulomatous tissue (Barbour et al 1981, Gkonos et al 1984, Zerwekh & Breslau 1986.…”

Uterine cells other than stromal decidual cells are required for 1,25‐dihydroxyvitamin D3 production during early human pregnancy

“…The control of extrarenal 1,25-(OH),D, synthesis appear to be different from that of the renal synthesis of [12,13]. In our experimental conditions, 1,25-(OH),D, production by human adherent decidual cells depends on the incubation medium used.…”

“…But the location and characterization of the cells responsible for this synthesis in the fetoplacental unit is not clear. Human trophoblastic tissue homogenates produce 1,25-(OH),D, in vitro [9,12,13], but not under all experimental conditions [8], and only when high substrate concentrations are used, 0.1-100 ,uM. Moreover, the K, of this production is higher, 570 nM [12], than that reported for 1,25-(OH),D3 production by kidney cells, 125 nM [15], and trophoblastic tissue may produce 1,25-(OH)2D, in vitro by a mechanism different from the classical one involving the cytochrome P450 mixed function oxidase [13].…”

“…This concept is based on experimental results showing that 1,25-(OH)*D3 is no longer formed after bilateral nephrectomy [l]. However, this is clearly not the case during pregnancy, as rat maternal blood contains 1,25-(OH),D, even after experimental bilateral nephrectomy [5,6], and as foeto-placental tissues from both animals and humans synthesize 1,25-(OH),D, in vitro [7-131. Studies on the ability of the human uterine cells to synthesize 1,25-(OH),D, have so far been mostly limited to the late pregnancy period [g-13], and/or have involved incubations with whole tissue homogenates [8,9,12,13]. The location and characterization of the cells responsible for the 1,25-(OH),D, synthesis in the feto-placental unit at this time of pregnancy remains a fertile field for debate [8-131.…”

“…The location and characterization of the cells responsible for the 1,25-(OH),D, synthesis in the feto-placental unit at this time of pregnancy remains a fertile field for debate [8-131. To date, an in vitro 1,25-(OH),D, production has been observed during incubations of placenta homogenate or mitochondria [9,12,13]. But this 1,25-(OH)*D3 production appears to *Corresponding author.…”