Calcidiol 1aHydroxylase

The active metabolite of vitamin D, calcitriol, is formed in the proximal tubules of the kidneys from calcidiol. There are three cytochrome P450-dependent enzymes in kidneys that catalyze 1-hydroxylation of calcidiol: CYP27A and CYP27 in mitochondria and a microsomal 1 a -hydroxylase, which is ferredoxin-dependent. It is likely that the microsomal enzyme is the most important; its synthesis is induced by cAMP in response to parathyroid hormone (Section and repressed by calcitriol (Omdahl et al., 2001; Wikvall, 2001).

Calcidiol 1a-hydroxylase is not restricted to the kidney, but is also found in placenta, bone cells (in culture), mammary glands, and keratinocytes. The placental enzyme makes a significant contribution to fetal calcitriol, but it is not clear whether the calcidiol 1-hydroxylase activity of other tissues is physiologically significant or not. Acutely nephrectomized animals given a single dose of calcidiol do not form any detectable calcitriol, but there is some formation of calcitriol in anephric patients, which increases on the administration of cholecalciferol or calcidiol. However, this extrarenal synthesis is not adequate to meet requirements, so that osteomalacia develops in renal failure (Section 3.4.1). The enzyme is inhibited, or possibly repressed, by strontium ions; this is the basis of strontium-induced vitamin D-resistant rickets, which responds to the administration of calcitriol or 1a-hydroxycalciol, but not calciferol or calcidiol (Omdahl and DeLuca, 1971).

Calcidiol 1a-hydroxylase also acts on 24-hydroxycalcidiol, yielding cal-citetrol; indeed, it has a relatively low specificity and will act on any secosteroid with hydroxyl groups at C-3 and C-25. Calcitriol has a short metabolic half-life after injection of the order of 4 to 6 hours (Holick, 1990). But, under normal conditions, the regulation of its synthesis means that the plasma concentration remains fairly constant, depending on the state of calcium balance (Hewison et al., 2000).

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