Several concepts have been proposed for the regulation of the regulation of the hydroxylation of 25-hydroxycholecalciferol (25-OH-D_3) in the kidney. The most prominent one is related to whether 25-OH-D_3 is converted to an active metabolite [1,25-(OH)_2-D_3] or to a nearly inert metabolite [24,25-(OH)_2-D_3]. The plasma levels of Ca, P and/or parathyroid hormone (PTH) have been suggested to be directly involved in this kind of metabolic regulation. Our results, however, clearly demonstrate that the regulation can proceed without changes in the plasma levels of Ca, P and possibly PTH, and that the level of 1,25-(OH)_2-D_3 in the body is the major factor which controls the adaptive response of the hydroxylation (1 or 24) of 25-OH-D_3. The regulation by 1,25-(OH)_2-D_3 levels seems to be related to induction or synthesis of 1-or 24-hydroxylases. Plasma levels of Ca, P and/or PTH appear to change the amount of intracellular Ca. The addition of 0.05〜0.2mM Ca to the kidney mitochondrial suspension caused a marked as well as dose-related stimulation of the 1-hydroxylation reaction. This stimulation coincided exactly with the increase in the amount of intramitochondrial Ca. We, therefore, propose that the level of 1,25-(OH)_2-D_3 in the body is related to the induction or synthesis of 1-and/or 24-hydroxylases, and that the amount of intramitochondrial Ca has a key role in the regulation of 1-hydroxylase activity in the kidney.
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