Feedback regulation of vitamin D metabolism by 1,25-dihydroxycholecalciferol

Abstract

Many factors influence the production of 1,25(OH)2D3 (1,25-dihydroxycholecalciferol) by the kidney. One important factor seems to be feedback regulation by 1,25(OH)2D3 itself. Administration of 1,25(OH)2D3 to vitamin D-deficient chicks abolishes renal 25(OH)D3(25-hydroxycholecalciferol)1-hydroxylase activity and induces the appearance of 25(OH)D3 24-hydroxylase activity. It is likely that these effects are mediated via a nuclear effect, as they are prevented by pretreatment with actinomycin D and alpha-amanitin. Further, 1,25(OH)2D3 has a marked effect on gene transcription in the kidney cell, as assessed by measurement of RNA polymerase activities. RNA polymerase I and II activities are 80-90% inhibited by 12.5nmol of 1,25(OH)2D3 within 30min of subcutaneous administration, indicating an immediate and massive decrease in total gene transcription. By 4h RNA polymerase II activity has returned to control values, but RNA polymerase I activity is markedly enhanced. These results are consistent with the view that regulation of cholecalciferol metabolism in the kidney is associated with an effect of the active metabolite on the kidney nucleus.

Plasma 1,25‐dihydroxyvitamin D levels in primary hyperparathyroidism depend on sex, body mass index, plasma phosphate and renal function

“…The increase in plasma calcium in PHPT may per se inhibit the renal 1α‐hydroxylase 2,3 . Furthermore, 1,25(OH) 2 D is known to inhibit its own synthesis as part of a negative feedback system 1,3 . Moreover, deficient vitamin D status 18 and increased body fat in PHPT 27,28 could reduce the plasma concentrations of the vitamin D metabolite 24–26 .…”

“…Cell-culture and whole-animal systems indicate that PTH and 1 α ,25-dihydroxyvitamin D [1,25(OH) 2 D)] are the most important regulators of the activity of the renal 25-hydroxyvitamin D [(25OHD)]-1 α -hydroxylase. [1][2][3] PTH increases the synthesis of 1,25(OH) 2 D, but 1,25(OH) 2 D inhibits its own production. In addition, high calcium may inhibit enzyme activity and phosphate restriction may directly enhance renal 1,25(OH) 2 D production, 3,4 whereas other hormones including oestrogen seem to influence calcium homeostasis indirectly.…”

“…Cell‐culture and whole‐animal systems indicate that PTH and 1α,25‐dihydroxyvitamin D [1,25(OH) 2 D)] are the most important regulators of the activity of the renal 25‐hydroxyvitamin D [(25OHD)]‐1α‐hydroxylase 1–3 . PTH increases the synthesis of 1,25(OH) 2 D, but 1,25(OH) 2 D inhibits its own production.…”

A possible role for CYP27 as a major renal mitochondrial 25‐hydroxyvitamin D3 1α‐hydroxylase

“…The activated vitamin D3 product, lct,25-dihydroxyvitamin D3, is known to regulate the 24-and la-hydroxylase activities reciprocally. Thus, CYP24 is induced whereas the mitochondrial ltx-hydroxylase activity in kidney is suppressed by this compound [8,[10][11][12][13]. CYP27 catalyzes 27-hydroxylation of C27-steroids and 25-hydroxyvitamin D3 and 25-hydroxylation of vitamin D3 in liver [10,14,15].…”

Vitamin D-dependent rickets type II. Defective induction of 25-hydroxyvitamin D3-24-hydroxylase by 1,25-dihydroxyvitamin D3 in cultured skin fibroblasts.

“…Renal (28)(29)(30)(31)(32)(33)(34)(35) as well as a variety of extrarenal tissues, including intestine (36), bone cells (37,38), and skin fibroblasts (13,14), have been shown to possess the enzyme 25(OH)D3-24-hydroxylase (24-OHase), which can be induced by 1,25(OH)2D; this induction appears to be mediated through the receptor for 1,25(OH)2D via a classical steroid hormone mechanism (34,35). Cultured skin fibroblasts from seven patients representing six kindreds with DD II have been evaluated and showed deficient 24-OHase induction by 1,25(OH)2D3 (13,14,19,20).…”