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J.-P. BARLET, B. ARGEMI, MARIE-JEANNE DAVICCO, and J. LEFAIVRE

I.N.R.A., Theix, 63110 Beaumont, France and Groupe Hospitalier de la Timone, 13385 Marseille, France

(Received 31 May 1978)

Very little information is available concerning interrelationships between maternal and foetal concentrations of 25-hydroxy vitamin D3 (25-OHD3; Hillman & Haddad, 1974; Ross, Care, Pickard, Peacock & Robinson, 1976; Weisman, Sapir, Harell & Edelstein, 1976). This paper describes the concentrations of 25-OHD3 in the plasma of pregnant and lactating ewes and their foetal and newborn lambs.

Five ewes bearing single lambs were selected by radiography performed on day 100 of gestation in winter. The daily intakes of calcium, phosphate and magnesium for each animal were respectively, 11, 7 and 2 g. From day 26 pre partum until day 4 post partum, blood samples were collected through catheters implanted on day 115 of gestation in the left foetal and maternal carotid arteries (Mellor & Matheson, 1975). Plasma concentrations of 25-OHD3

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PM Bourlon, A Faure-Dussert, and B Billaudel

Since both the release and de novo biosynthesis of insulin are severely decreased by vitamin D3 deficiency and improved by 1, 25-dihydroxyvitamin D3 (1,25(OH)2D3) repletion following a 6-h delay in the rat, the present experiments investigated the effects of vitamin D3 deficiency on the biosynthesis of heavier molecular weight proteins using electrophoretic separation. Gel protein staining by Coomassie blue showed very different profiles for islets protein production from 4-week vitamin D3-deficient rats compared with normal islets. The pattern was characterised by a decrease in high molecular weight proteins, concomitantly accompanied by an increase in low molecular weight proteins. This tendency was partially reversed in vivo by 1,25(OH)2D3 repletion treatment for 7 days and was evident after only 16 h of treatment. In parallel with these in vivo observations, which represent a static index of islets protein production, a kinetic study was performed in vitro by a double-labelling method allowing us to measure the de novo synthesis of proteins in islets during a strong 16.7 mM glucose stimulation. Comparison of 3H and 14C labelled samples was achieved via coelectrophoresis to avoid experimental artefacts. The study of the ratio of d.p.m. 3H/d.p.m. 14C for each molecular weight protein in islets stimulated by 16.7 mM glucose (versus basal 4.2 mM glucose) showed an increase in the height of certain peaks: 150, 130 and 8.5 kDa. Under the same conditions, islets from 4-week vitamin D3-deficient rats (versus normal islets) presented a large deficit of numerous newly synthesised proteins and particularly those implicated in the response to glucose stimulation. In vitro repletion of 1,25(OH)2D3 tended to reverse, at least in part, the deleterious effect of vitamin D3 deficiency on the de novo protein synthesis of islets but these effects were gradual. Indeed, there was no detectable effect at 2 h incubation, but 1,25(OH)2D3 increased the 60 to 65 kDa, 55 kDa, and 9 to 8 kDa molecular mass proteins at 4 h, and increased the level of most newly synthesised proteins at 6 h. These data support the hypothesis of a beneficial genomic influence of 1,25(OH)2D3 that occurs progressively within the islets of Langerhans and which may prepare the beta cells for an enhanced response to glucose stimulation.

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H. PAVLOVITCH, O. FONTAINE, and S. BALSAN

The metabolism of 25-hydroxycholecalciferol (25-(OH)D3) was investigated in rats fed a diet low in calcium and without vitamin D for 4 weeks after hypophysectomy. Compared with intact rats on the same diet these animals had a low serum phosphorus concentration, a less marked degree of hypocalcaemia and their parathyroid gland was not hypertrophied. Eighteen hours after i.p. injection of a single dose of tritiated 25-(OH)D3, chromatography of serum extracts on Sephadex LH-20 showed that the percentage of radioactivity corresponding to 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) was lower in hypophysectomized rats than in control rats. High-pressure liquid chromatography demonstrated that 81% of this material had the same elution profile as synthetic 1,25-(OH)2D3. The percentage of 1,25-(OH)2D3 in the serum of hypophysectomized rats could be increased to the level seen in the controls by chronic treatment with bovine growth hormone. This action of growth hormone was most probably independent of the parathyroid glands since the injection of parathyroid extract did not alter 25-(OH)D3 metabolism in hypophysectomized animals. These results suggest that the decrease in the conversion of 25-(OH)D3 to 1,25-(OH)2D3 after hypophysectomy may be related to the lack of growth hormone.

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C Farquharson, J S Rennie, N Loveridge, and C C Whitehead

Abstract

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is regarded as the most biologically active metabolite of cholecalciferol. It prevents tibial dyschondroplasia (TD) in chicks where inhibition of chondrocyte differentiation within the growth plate occurs. However, it is unclear whether its mode of action is through direct interaction with its chondrocyte receptor and its known regulatory role in cell differentiation or is mediated by increased calcium absorption and mobilisation. Synthetic analogues of 1,25(OH)2D3 such as 1,25-dihydroxy-16-ene-23-yne cholecalciferol (RO 23–7553) with increased differentiation properties but reduced calcaemic activity have been synthesised. In this study, the in vitro and in vivo effects of 1,25(OH)2D3 and RO 23–7553 on chick chondrocyte growth and differentiation were examined. In addition, the in vivo effectiveness of these steroids in preventing TD in chicks was assessed. 1,25(OH)2D3 and RO 23–7553 (10−12-10−7 m) displayed biphasic concentration effects and had similar potencies in vitro in regulating chondrocyte proliferation and differentiation. However, while the incidence of TD in birds dosed with 1,25(OH)2D3 was lower (10%) than in control chicks (55%), RO 23–7553 was ineffective (50%). This may be the result of its reduced affinity (1000 times less) for the plasma vitamin D binding protein (DBP) and the chondrocyte receptor in comparison to that of 1,25(OH)2D3. A reduction in calcium supply to the chondrocyte may also result in decreased chondrocyte differentiation but blood ionised and plasma total calcium were normal in birds dosed with RO 23–7553. These data suggest that RO 23–7553 and 1,25(OH)2D3 regulate chondrocyte proliferation and differentiation similarly in vitro but not in vivo. This may be caused by differences in DBP binding and clearance rates of the two steroids in vivo.

Journal of Endocrinology (1996) 148, 465–474

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T Nickerson and H Huynh

Vitamin D analogues have an antiproliferative effect on prostate cancer cells in vitro and thus have been proposed as candidates for chemoprevention of prostate cancer. Insulin-like growth factor (IGF)-I has been shown to protect cells from apoptosis and plays an essential role in normal prostate physiology. We have studied the effects of the 1,25-dihydroxyvitamin D3 analogue EB1089 on the IGF system in the prostate in vivo. Treatment of rats with EB1089 for 14 days caused a 25% decrease in ventral prostate weight. Apoptosis was detected in prostate sections of EB1089-treated rats by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling(TUNEL) assay and histologic examination of hematoxylin/eosin stained tissue sections indicated that secretory epithelial cells were flattened, a characteristic of cells undergoing pressure-induced atrophy. Ventral prostate regression was associated with 15- to 25-fold increases in gene expression of IGF-binding proteins (IGFBPs)-2,-3,-4 and -5. We also observed a 40-fold increase in prostatic IGF-I mRNA levels in response to EB1089. Although we have previously shown that castration of rats leads to upregulation of IGFBPs in the ventral prostate, EB1089 treatment had no effect on serum levels of dihydrotestosterone or free testosterone. These results suggest that prostate regression induced by EB1089 may be related to alterations in availability of IGF-I as a result of increased production of IGFBPs.

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R Gniadecki

Abstract

The cellular signalling pathways of a potent 20-epi-22-oxa vitamin D3 analogue (KH 1060) were examined in vivo in a hairless mouse model. Seventy two hours after a single topical application of KH 1060 a thickening of the epidermis (from 24·8 ±1·2 μm at 0·01 pmol/cm2 KH 1060 to 124·2 ± 6 μm at 5 pmol/cm2 KH 1060, P<0·001) was elicited due to epidermal hyperproliferation. This effect could be blocked by topical 2·5 μmol/cm sphingosine, an inhibitor of protein kinase C. Two hours after topical application of 2·5 pmol/cm2 KH 1060 a translocation of protein kinase C activity from cytoplasm to the membrane fractions was observed. Moreover, using a reverse-transcription polymerase chain reaction technique, a transient upregulation of c-fos gene expression was seen 2 hours after topical treatment with KH 1060. The expression of c-fos was dependent on protein kinase C activation, since after pretreatment with the protein kinase C blocker sphingosine, c-fos messenger RNA was not detected. These findings strongly suggest that KH 1060 stimulates epidermal growth through activation of the protein kinase C - c-fos signalling axis in vivo.

Journal of Endocrinology (1994) 143, 521–525

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J. FOX and A. D. CARE

The effects of hydroxylated derivatives of vitamin D3 and aqueous extracts of Solanum malacoxylon on the intestinal absorption of calcium, phosphate, sodium, potassium and water have been studied in unstressed vitamin D-replete pigs each of which was surgically prepared beforehand with a Thirty–Vella loop of jejunum. The addition, for six 1 h periods of perfusion, of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) or 1α-hydroxycholecalciferol at similar concentrations (3·6–3·75 pmol/ml) to the solution used to perfuse the intestinal loop caused a rapid increase in the absorption of calcium but increased the absorption of phosphate only after a delay of at least 12 h. The absorption of both calcium and phosphate reached a maximum on the day following the addition of the vitamin D derivative to the perfusate. The addition of 25-hydroxycholecalciferol (25-(OH)D3) at a concentration of 3·75 pmol/ml was without effect on absorption except for a small increase in the absorption of phosphate on the following day. However, at higher concentrations (> 250 pmol 25-(OH)D3/ml) the absorptions of calcium and phosphate were both increased rapidly. 24,25-Dihydroxycholecalciferol was without effect on absorption at the concentration tested (3·6 pmol/ml).

Aqueous extracts (1%) of the leaf of S. malacoxylon showed similar effects on absorption to those of 1,25-(OH)2D3. However, there was one point of difference; the absorption of phosphate was stimulated with a similar time course to that of calcium in contrast to its delayed response to 1,25-(OH)2D3.

The absorption rates of water, sodium and potassium were not consistently affected by 1,25-(OH)2D3 or S. malacoxylon. However, the major effects of these derivatives were usually seen on the day following the day of addition to the perfusate. In contrast, 25-(OH)D3 at high concentrations had a marked effect on the absorption of water, sodium and potassium on the day of addition.

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Juan Kong, Yunzi Chen, Guojun Zhu, Qun Zhao, and Yan Chun Li

other functions such as reproduction and immunity ( Donato et al . 2011 , Procaccini et al . 2012 ). The vitamin D hormone is a pleiotropic hormone that has a broad range of physiological functions ( Bouillon et al . 2008 ). The active form of

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Gideon S Bevelander, Elsa S L C Pinto, Adelino V M Canario, Tom Spanings, and Gert Flik

Introduction Vitamin D 3 requires transformations to become bioactive. These transformations involve cytochrome P450 (CYP) enzymes that hydroxylate the steroid. In mammals, the most abundant source of CYP enzymes is the liver, where a first

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C. J. Robinson, E. Spanos, M. F. James, J. W. Pike, M. R. Haussler, A. M. Makeen, C. J. Hillyard, and I. MacIntyre

Intestinal calcium absorption and plasma levels of 1,25-dihydroxycholecalciferol (1,25(OH)2D3) were measured in lactating and non-lactating rats and the effects of bromocriptine and exogenous prolactin treatment were evaluated. In lactating rats calcium absorption and plasma levels of parathyroid hormone, 1,25(OH)2D3 and alkaline phosphatase activity were significantly increased. Bromocriptine treatment significantly reduced the enhanced calcium absorption and levels of plasma 1,25(OH)2D3 and alkaline phosphatase but had no significant effect on plasma levels of parathyroid hormone. Prolactin administered with bromocriptine to lactating animals prevented all the changes observed with bromocriptine treatment alone. It was concluded that the increased plasma levels of prolactin during lactation lead to high plasma levels of 1,25(OH)2D3 which are responsible for the enhanced intestinal calcium absorption.