Dissociation of phosphaturia and 25(OH)D-1 alpha-hydroxylase trophism using a novel analogue of parathyroid hormone

1992 ◽  
Vol 262 (4) ◽  
pp. E483-E487 ◽  
Author(s):  
T. O. Carpenter ◽  
M. D. McPhee ◽  
R. Bort ◽  
M. A. Mitnick ◽  
D. L. Carnes
Keyword(s):  
Parathyroid Hormone ◽  
High Performance ◽  
Phosphate Transport ◽  
Hydroxylase Activity ◽  
Renal Handling ◽  
Hydroxyvitamin D ◽  
C57bl Mice ◽  
25 Hydroxyvitamin D ◽  
Stimulation Of

Certain parathyroid hormone (PTH) analogues have been shown to selectively impair some but not all physiological actions of PTH. In this study, transaminated rat (r) PTH [TA-rPTH-(1-34)], a PTH analogue that differs from the rPTH-(1-34) fragment in that the NH2-terminal alanine is converted to pyruvate, was infused into mice to determine its properties in vivo and specifically to determine whether stimulation of 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-hydroxylase) activity was more dependent on concomitant renal handling of phosphate or on generation of adenosine 3',5'-cyclic monophosphate (cAMP). High-performance liquid chromatography-purified TA-rPTH-(1-34) was infused into C57BL mice at 10 or 30 pmol/h for 24 h. At 30 pmol/h, TA-rPTH-(1-34) was comparable with rPTH-(1-34) in its hypophosphatemic and phosphaturic effects but was less potent than rPTH-(1-34) in raising serum calcium. TA-rPTH-(1-34) was markedly less effective in stimulating renal 1 alpha-hydroxylase than rPTH-(1-34). Stimulation of urinary cAMP excretion occurred after infusion with TA-rPTH-(1-34), but this effect was significantly less than that seen with rPTH-(1-34). These findings indicate that PTH-induced hypophosphatemia and phosphaturia can be uncoupled from PTH stimulation of 1 alpha-hydroxylase. Furthermore, cAMP-related signal transduction appears to be more significant in regulation of 1 alpha-hydroxylase than mechanisms that mediate PTH-sensitive phosphate transport, independent of cAMP.

Effect of parathyroid hormone-like peptides on 25-hydroxyvitamin D-1 alpha-hydroxylase activity in rodents

1990 ◽  
Vol 258 (2) ◽  
pp. E297-E303 ◽  
Author(s):  
A. T. Walker ◽  
A. F. Stewart ◽  
E. A. Korn ◽  
T. Shiratori ◽  
M. A. Mitnick ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Maximal Activity ◽  
Hydroxylase Activity ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Vitamin D Metabolism ◽  
Control Activity ◽  
Humoral Hypercalcemia ◽  
Stimulation Of

The role of vitamin D metabolism in the humoral hypercalcemia of malignancy syndrome (HHM) is unclear. We studied in vivo and in vitro effects of synthetic parathyroid hormone-like peptides (PTH-LPs) on rodent renal 25-OHD-1 alpha-hydroxylase activity. Infusion of mice with PTH-LP-(1-36) at 10 pmol/h for 12 and 24 h showed significant (429 +/- 139% and 937 +/- 413%, respectively) stimulation of control enzyme activity. Infusion for 36 h demonstrated diminution of activity to levels nearer to the unstimulated state (228 +/- 36% of control). In that maximal activity was observed after 24 h of infusion, we examined 1 alpha-hydroxylase activity after variable dosages of PTH-LP-(1-36) at this time point. Animals infused with PTH-LP-(1-36) at dosages of 2.5, 10, and 30 pmol/h for 24 h demonstrated 1 alpha-hydroxylase activities of 0.71 +/- 0.12, 4.74 +/- 2.09, and 9.91 +/- 1.01 ng.mg protein-1.20 min-1 (means +/- SD), respectively, all significantly greater than control activity (0.51 +/- 0.20 ng.mg protein-1.20 min-1). PTH-LP-(1-36) and PTH-LP-(1-74) were comparable in potency to bovine (b)PTH-(1-34) in stimulating 1 alpha-hydroxylase. Direct in vitro incubation of PTH-LP-(1-36) with renal slices resulted in stimulation of 1 alpha-hydroxylase activity up to 200% of control levels, comparable to that seen with equimolar concentrations of bPTH-(1-34).(ABSTRACT TRUNCATED AT 250 WORDS)

Differential behaviour of 25-hydroxyvitamin D3 24-hydroxylase and 1-hydroxylase in response to protein synthesis inhibitors and cytochrome P-450 inhibitors

1988 ◽  
Vol 66 (5) ◽  
pp. 586-591 ◽  
Author(s):  
M. Kung ◽  
S. W. Kooh ◽  
W. Paek ◽  
D. Fraser
Keyword(s):  
Protein Synthesis ◽  
Enzyme Activities ◽  
Protein Synthesis Inhibitors ◽  
Hydroxylase Activity ◽  
Hydroxyvitamin D ◽  
Control Value ◽  
25 Hydroxyvitamin D ◽  
Cytochrome P 450

To characterize 25-hydroxyvitamin D3 24-hydroxylase and 25-hydroxyvitamin D3 1-hydroxylase, the activities of the two enzymes were measured in the presence of two types of inhibitors. The effect of protein synthesis inhibitors on 25-hydroxyvitamin D3-stimulated 24-hydroxylase activity in 1-hydroxylating rat kidneys perfused in vitro was tested. Actinomycin D (4 μM) and cytoheximide (10 μM) each abolished 25-hydroxyvitamin D3 24-hydroxylase synthesis when added at the start of perfusion but not when added 4 h later; they did not affect 25-hydroxyvitamin D3 1-hydroxylase activity. The effects of cytochrome P-450 inhibitors on the two enzyme activities were then studied in vivo. Metyrapone and SKF-525A (50 mg/kg body weight) each inhibited 25-hydroxyvitamin D3 24-hydroxylase at 6 and 24 h; in contrast 1-hydroxylase increased and was 5 times the control value at 24 h. Finally, the in vitro effects of six cytochrome P-450 inhibitors at concentrations ranging from 10−7 to 10−3 M on enzyme activities in renal mitochondrial preparations were compared. Both enzymes were inhibited by all of the inhibitors, but inhibition of 25-hydroxyvitamin D3 24-hydroxylase was consistently greater than that of 25-hydroxyvitamin D3 1-hydroxylase. These studies demonstrate that 24-hydroxylation and 1-hydroxylation respond differently to protein synthesis inhibitors and to cytochrome P-450 inhibitors. The findings are consistent with the hypothesis that the two enzyme activities are associated with different cytochrome P-450 moieties.

Evaluation of a parathyroid hormone antagonist in an in vivo multiparameter bioassay

1987 ◽  
Vol 253 (2) ◽  
pp. E187-E192
Author(s):  
N. Horiuchi ◽  
M. Rosenblatt
Keyword(s):  
Parathyroid Hormone ◽  
Dependent Manner ◽  
Hydroxylase Activity ◽  
Dose Ratio ◽  
Hormone Analogue ◽  
Potent Antagonist ◽  
Dose Dependent ◽  
Bovine Parathyroid Hormone ◽  
Stimulation Of

The antagonist properties of a bovine parathyroid hormone analogue ([Tyr34]bPTH-(7-34] amide were quantitatively assessed in vivo in a multiparameter assay to estimate the potency of the antagonist against the major actions of PTH. The analogue inhibited PTH-stimulated urinary excretion of phosphate and adenosine 3',5'-cyclic monophosphate in vitamin D-deficient thyroparathyroidectomized rats in a dose-dependent manner. At a molar dose ratio as low as 5:1 of antagonist to PTH, partial inhibition occurred. PTH stimulates the activity of 25-hydroxyvitamin D3-1 alpha-hydroxylase in renal proximal tubules. When coinfused with PTH, this analogue completely inhibited PTH-stimulated 1 alpha-hydroxylase activity at a molar dose ratio of 25:1 of antagonist to PTH and partially inhibited the activity at a molar dose ratio of 10:1. The analogue revealed no PTH-like agonist activity for stimulation of the 1 alpha-hydroxylase. Taken together, these studies indicate that [Tyr34]bPTH-(7-34) amide is a potent antagonist of several of the parameters of PTH action in vivo and demonstrate the feasibility of designing a PTH antagonist that can interact simultaneously with all the PTH receptors responsible for the hormone's major actions in vivo.

Parathyroid hormone-independent regulation of 1,25(OH)2D in response to inhibition of bone resorption

1988 ◽  
Vol 254 (3) ◽  
pp. E260-E264
Author(s):  
J. P. Bonjour ◽  
U. Trechsel ◽  
C. M. Taylor ◽  
H. Fleisch
Keyword(s):  
Parathyroid Hormone ◽  
Bone Resorption ◽  
Marked Rise ◽  
Absorption Increase ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
25 Hydroxyvitamin D ◽  
Intestinal Ca Absorption ◽  
Homeostatic Response ◽  
Stimulation Of

Both plasma level of 1,25-dihydroxyvitamin D [1,25(OH)2D] and intestinal Ca absorption increase after biphosphonate-induced inhibition of bone resorption. Parathyroid hormone (PTH) has been considered a key mediating element of this homeostatic response. In the present work, the role of PTH was assessed by studying the influence of 1-hydroxypentane-1,1-bisphosphonate (HPeBP) on vitamin D and Ca metabolism in both intact and thyroparathyroidectomized (TPTX) rats. In intact rats, HPeBP given at 0.1 mg P/kg body wt sc for 10 days strongly inhibited bone resorption without affecting bone formation. This effect was associated with a marked stimulation of intestinal Ca absorption and Ca balance. In this condition, HPeBP caused a marked rise in plasma 1.25(OH)2D without affecting the level of 25-hydroxyvitamin D. In TPTX rats, HPeBP given at same dose also inhibited bone resorption and enhanced plasma 1,25(OH)2D, intestinal Ca absorption and Ca balance. In summary, this study shows that bisphosphonates such as HPeBP with prevailing inhibitory activity on bone resorption induce a marked stimulation of both 1,25(OH)2D production and intestinal Ca absorption. This homeostatic response is not attenuated after PTH removal. Thus, as previously shown for the response to low Ca diet, PTH does not appear to be an essential mediating factor for stimulating 1,25(OH)2D production in response to an increase in bone mineral retention.

Is hydrochlorothiazide-induced hypocalciuria due to inhibition of prostaglandin E2 synthesis?

1990 ◽  
Vol 78 (3) ◽  
pp. 321-325 ◽  
Author(s):  
Lorenzo Caló ◽  
Salvatore Cantaro ◽  
Francesco Marchini ◽  
Sandro Giannini ◽  
Rocco Castrignano ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Prostaglandin E2 ◽  
Percentage Change ◽  
Idiopathic Hypercalciuria ◽  
Hydroxylase Activity ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Stone Formers ◽  
25 Hydroxyvitamin D

1. Since prostaglandin E2 could play a role in idiopathic hypercalciuria, and considering the well-established hypocalciuric action of hydrochlorothiazide, we have evaluated the effect of 15 days' treatment with hydrochlorothiazide in 10 hypercalciuric male stone-formers on urinary Ca2+ and prostaglandin E2, as well as on plasma bicyclo-prostaglandin E2, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and parathyroid hormone. 2. In addition to lowering urinary Ca2+ (P <0.001), hydrochlorothiazide also promoted a significant fall in urinary prostaglandin E2 (P <0.001), plasma bicyclo-prostaglandin E2 (P <0.001) and 1,25-dihydroxyvitamin D (P <0.01), and an increase in plasma parathyroid hormone (P <0.025), whereas plasma 25-hydroxyvitamin D was unchanged. 3. A positive correlation between urinary Ca2+ and prostaglandin E2 was present before (P <0.00005), but not after, hydrochlorothiazide. Plasma bicyclo-prostaglandin E2 and plasma 1,25-dihydroxyvitamin D were positively correlated both before (P <0.005) and after (P <0.005) hydrochlorothiazide, as was also the percentage change in each induced by the drug (P <0.05). Furthermore, the changes in plasma 25-hydroxyvitamin D and plasma 1,25-dihydroxyvitamin D after hydrochlorothiazide were negatively correlated (P <0.05). 4. It is suggested that a block of prostaglandin E2 synthesis plays a role in the effect of hydrochlorothiazide on Ca2+ metabolism, most probably through an inhibition of 1α-hydroxylase activity.

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