There are two separate cytochrome P450-dependent mixed-function oxidases in the liver that catalyze the 25-hydroxylation of cholecalciferol (see Figure 3.3). The activity of both enzymes is higher in tissue from vitamin D-deficient animals, and there is some evidence that calcitriol either inhibits or represses them. The mitochondrial enzyme (CYP27A), which has a Km of 10-5 M, catalyzes the hydroxylation of cholecalciferol twice as fast ergocalciferol. It also acts on a number of C-27 steroids and is involved in bile acid synthesis. This enzyme requires ferredoxin and ferredoxin reductase for activity. The microsomal enzyme (CYP2D25), with a Km of 10-7 M, only acts on cholecalciferol, and not ergocalciferol, although it also acts on a number of C-27 steroids and will catalyze the 25-hydroxylation of 1a-hydroxycholecalciferol (hydroxycal-ciol) to calcitriol. As discussed in Section 3.4.2, this has been exploited to treat and prevent problems of vitamin D-resistant rickets and osteomalacia in cases of renal failure (renal osteodystrophy) using 1a-hydroxycholecalciferol.
Figure 3.3. Metabolism of calciol to yield calcitriol and 24-hydroxycalcidiol.
Cholecalciferol 25-hydroxylase is not restricted to the liver; kidneys, skin, and gut microsomes also have a cytochrome P450 -dependent enzyme that catalyzes the 25-hydroxylation of cholecalciferol and 1a-hydroxycholecalciferol, but not ergocalciferol. Although there is some evidence that calcitriol can reduce the activity of calciferol 25-hydroxylase, it is not known whether this is physiologically important; the major factor controlling 25-hydroxylation is the rate of uptake of cholecalciferol into the liver. It is the fate of calcidiol in the kidneys that provides the most important regulation of vitamin D metabolism (Wikvall, 2001).
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