Pathway maps

Vitamin D2 (ergocalciferol) metabolism

The first step of Vitamin D2 metabolism is a side-chain hydroxylation in the liver carried out by specific cytochrome P450 enzymes. The hydroxylation reactions can be catalyzed by Cytochrome P450, family 3, subfamily A, polypeptide 4 ( CYP3A4 ) [1], [2] and Cytochrome P450, family 27, subfamily A, polypeptide 1 ( CYP27A1 ) [3], [4], [5], [6], [2] and result in formation of 24-OH-vitamin D2 metabolite. Alternatively the reactions can be catalyzed by CYP27A1 [7], CYP3A4 [1], [2], Cytochrome P450, family 2, subfamily C, polypeptide 9 ( CYP2C9 ) [1] and cytochrome Cytochrome P450, family 2, subfamily R, polypeptide 1 ( CYP2R1 ) [7], [1], [2] to produce 25-OH-vitamin D2 metabolite.

Vitamin D2 analogue Doxercalciferol is also hydroxylated by CYP27A1 and CYP3A4 to form 1,24-Dihydroxyvitamin D2 [5], [6], [1], [2] and 1,25-Dihydroxyvitamin D2 [1], [2] as products. The latter metabolites are also formed during the subsequent metabolic steps in kidney. In particular, 1,24-Dihydroxyvitamin D2 and 1,25-Dihydroxyvitamin D2 are products of hydroxylation of, respectively, 24-OH-vitamin D2 and 25-OH-vitamin D2 catalyzed by Cytochrome P450, family 27, subfamily B, polypeptide 1 ( CYP27B1 ) [4], [6], [2].

1,24-Dihydroxyvitamin D2 is further hydroxylated by CYP27A1 and cytochrome Cytochrome P450, family 24, subfamily A, polypeptide 1 ( CYP24A1 ) to form a 1-alpha,24,26-trihydroxy-vitamin D2 trihydroxylated metabolite [5], [8] that undergoes subsequent oxidation at C-26 catalyzed by CYP24A1 [8], [9] with 1alpha-,24-dihydroxy-26-carboxy-vitamin D2 as a product.

25-OH-vitamin D2 can be further hydroxylated by CYP24A1 when a 24,25-Dihydroxyvitamin D2 metabolite is formed [6].

The same P450 enzyme catalyzes all further steps of 1,25-Dihydroxyvitamin D2 degradation that include: hydroxylation at C-24 to form 1-alfa-,24-,25-(OH)3-vitamin D2 as a product and subsequent hydroxylation at C-28 to form 1-alfa-,24-,25-,28-(OH)4-vitamin D2. The following hydroxyl group migration results in production of stereo isomers of which only 1-alfa-,24(R)-,25-,26-Tetrahydroxy-Vitamin D2 participates in C-24 hydroxyl group oxidation to form 1alfa-,25-,26-trihydroxy-24-oxo-vitamin D2 metabolite. This metabolite is then hydroxylated to 1alpha-,23-,25-,26-tetrahydroxy-24-oxo-vitamin D2 and undergoes a side-chain degradation to 1,23-Dihydroxy-24,25,26,27-tetranorvitamin D3. At the final stage, the latter metabolite is oxidized to form Calcitroic acid.