1. The metabolism of an intravenous pulse-dose of 65 nmol (25 μg) of double-isotope-labelled cholecalciferol has been studied in 28 individuals. The subjects comprised 19 with serum concentrations of 25–hydroxycalciferol (25–(OH)D) ≤ 25 nmol/l, of whom 12 had clinical osteomalacia, and nine with serum 25–(OH)D > 25 nmol/l (30–125 nmol/l).

2. The concentrations in serum of radioactive cholecalciferol, 25–hydroxycholecalciferol (25–(OH)D3) and the three dihydroxylated metabolites: 1,25–, 24,25– and 25,26–dihydroxycholecalciferol (1,25–(OH)2D3, 24,25-(OH)2D3 and 25,26–(OH)2D3) were measured for up to 10 days after the injection.

3. The temporal relationships between the formation of individual radioactive metabolites and factors apparently influencing their production are described and their molar concentrations in serum calculated.

4. Formation of radioactive 1,25-(OH)2D3 was detectable only in vitamin D—deficient subjects. Between individuals, its maximum serum concentration was correlated significantly and inversely with serum calcium but with no other measured variable. In the individual, concentrations of radioactive serum 1,25-(OH)2D3 varied directly with radioactive serum 25-(OH)D3.

5. The failure to detect formation of radioactive 1,25–(OH)2D3 in vitamin D—replete subjects suggests that current estimates of the daily turnover of the hormone in the normal individual may be severalfold too high.

6. Radioactive 25,26–(OH)2D3 was produced rapidly by all subjects and in greater amounts by vitamin D—deficient individuals. Between subjects and in the individual its concentration in serum correlated only with the radioactive serum 25–(OH)D3. Production of this metabolite appeared to be unregulated and dependent solely on the concentration of its precursor.

7. In vitamin D—replete subjects, production of 24,25–(OH)2D3 was also apparently determined by precursor concentration. In vitamin D—depleted subjects, production of radioactive 24,25–(OH)2D3 was variably delayed for up to or more than 10 days.

8. There appeared to be a constraint on the quantitative hepatic production of 25–(OH)D which is not explained by simple feed—back inhibition.

9. If sterols other than 1,25–(OH)2D3 are required to initiate the mineralization of osteomalacic bone, after correction of vitamin D deficiency in man, 25–(OH)D3 and 25,26–(OH)2D3 are produced sufficiently rapidly to meet this hypothetical requirement, but not 24,25–(OH)2D3.

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