Hypercalcemic activity

The activities of la,25(OH)2D4 on a calcium transport and bone mobilization in vitamin D deficient SD rats were less than (about 1/2) those of la,25(OH)2D3. This is well understood by stronger affinity of la,25(OH)2D4 for DBP than that of la,25(OH)2D3 because of the decreased availability for target cells (decreased uptakes into the cells)[43,44], The hypercalcemic activities of 24-epi-la,25(OH)2D2 and la,25(OH)2D7 were negligible as compared with that of la,25(OH)2D3. Their effects on intestinal calcium transport was significantly smaller than that of la,25(OH)2D3 and it is required 10 fold more of these compounds to produce a similar activity to la,25(OH)2D3 [35]. 

A less common circumstance leading to hypercalcemia is development of a form of bone disease characterized by a profound decrease in bone cell activity and loss of the calcium buffering action of bone (adynamic bone disease). In the absence of kidney function, any calcium absorbed from the intestine accumulates in the blood. Therefore, such patients are very sensitive to the hypercalcemic action of l,25(OH)2D. These individuals generally have a high serum calcium but... 

It seems to be fully established that the thyroid gland in many animal species contains a substance or substances (thyrocalcitonin) able to lower the plasma calcium concentration, and secreted in response to the passage of hypercalcemic blood through the gland. Potent extracts can be prepared, and are active when injected or infused into normal and parathyroidectomized animals. This substance is quite distinct from thyroid hormone. 

The humoral hypercalcemia of malignancy hypothesis states that an osteolytic non-PTH substance is secreted by certain tumors and, in an endocrine manner, is transported from tumor to bone through the bloodstream. The evidence for this hypothesis is that 1) bone destruction occurs in patients without bone metastases, 2) serum PTH levels in these patients were usually normal, 3) PTH mRNA was absent in tumors (27), and 4) tumor extracts from hypercalcemic patients enhanced bone cell adenylate cyclase activity and phosphate transport in kidney epithelial cells (28-30). 

It was Boyle (25) in 1971 who first demonstrated that under normal or hypercalcemic conditions a major circulating metabolite of 25-hydroxyvitamin D3 is 24,25-dihydroxyvitamin D3 (5). He claimed in 1973 (27) that 24,25-dihydroxyvitamin D3 is capable of inducing intestinal calcium transport at dose levels similar to that of la,25-dihydroxyvitamin D3 but has little ability to cause bone resorption and further showed that 24,25-dihydroxyvitamin D3 was metabolized to a more potent metabolite in the kidney before these activities were observed. DeLuca (76) in 1973 showed that in chickens this more potent metabolite was la,24,25-trihydroxy-vitamin D3 (6), although the configuration at the 24-position was not defined at this time, and that in chickens (6) was only 60 percent as active as vitamin D3 in curing rickets and was less active than la,25-dihydroxy-vitamin D3 in stimulating and sustaining intestinal calcium transport and bone resorption. He further indicated that this mixime of 24-isomers had preferential action on the intestine and did not cause bone resorption as much as was expected. More recently, Uskokovic (143) has chemically... 

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