REGULATION OF VITAMIN D METABOLISM

The metabolic activation of vitamin D is subject to both coarse-and fine-control mechanisms operating at the principal enzymatic steps.17 Hepatic 25-hydroxylation is more efficient at low levels of substrate, and the absolute amount of 25(OH)D in the circulation declines when the supply of vitamin D increases. Nevertheless, the degree of regulation of 25(OH)D synthesis is not sufficient to prevent vitamin D intoxication after the ingestion of large amounts of vitamin D.18

In contrast to the relatively coarse control of hepatic 25- hydroxylation, renal 1 α-hydroxylation is regulated strictly and represents the most important regulatory mechanism in the metabolism of vitamin D. In normal adults, serum concentrations of 1,25(OH)₂D change little in response to repeated dosing with vitamin D, and remain normal or even decline in vitamin D intoxication. The three major factors that regulate the enzyme’s activity are blood parathyroid hormone (PTH), calcium, and phosphorus.

PARATHYROID HORMONE

Parathyroid hormone is the main hormonal stimulus for 1 α-hydroxylation, increasing systemic 1,25(OH)₂D levels after administration to human research subjects.19 Hypocalcemia also stimulates 1 α-hydroxylation, but this effect is achieved largely through a feedback loop (see Chap. 58) involving the parathyroid glands17; hypocalcemia stimulates PTH secretion, which raises serum 1,25(OH)₂D concentrations. 1,25(OH)₂D enhances calcium absorption, and the increased serum calcium concentration then inhibits PTH secretion (Fig. 54-4). Some experimental studies suggest that the extracellular calcium concentration can directly influence the renal 1 α-hydroxylase.

FIGURE 54-4. Effect of a decline in plasma calcium on circulating parathyroid hormone and 1,25(OH)₂D concentrations in humans. Eight patients with Paget disease received plicamycin (25 μg/kg) by infusion. This resulted in a sudden reduction of plasma calcium levels followed by an increase in parathyroid hormone and 1,25(OH)₂D₃ concentrations. (AMP, adenosine monophosphate.) (Modified from Bilezikian JP, Canfield RE, Jacobs JP. Response of 1 α-dihydroxyvitamin D₃ to hypocalcemia in human subjects. N Engl J Med 1978; 299:437.)

PHOSPHORUS

The blood phosphorus concentration is the third major control factor. In rats and in humans, hypophosphatemia stimulates 1 α-hydroxylase activity and increases the 1,25(OH)₂D concentration in serum, whereas hyperphosphatemia inhibits formation of the metabolite (see Fig. 54-4). This adaptive effect does not depend on PTH, but it may require insulin-like growth factor-I.20

Only gold members can continue reading. Log In or Register to continue