Vitamin D2 (ergocalciferol) metabolism

Vitamin D2 (ergocalciferol) metabolism

The first step of Vitamin D2 metabolism is a side-chain hydroxylation in theliver carried out by specific cytochrome P450 enzymes. The hydroxylation reactions can becatalyzed 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 D2metabolite. Alternatively the reactions can be catalyzed by CYP27A1 [7], CYP3A4 [1], [2], Cytochrome P450, family 2,subfamily C, polypeptide 9 ( CYP2C9 ) [1] and cytochrome CytochromeP450, 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 andCYP3A4 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 thesubsequent metabolic steps in kidney. In particular, 1,24-Dihydroxyvitamin D2 and1,25-Dihydroxyvitamin D2 are products of hydroxylation of, respectively,24-OH-vitamin D2 and 25-OH-vitamin D2 catalyzed by Cytochrome P450, family27, subfamily B, polypeptide 1 ( CYP27B1 ) [4], [6],[2].

1,24-Dihydroxyvitamin D2 is further hydroxylated by CYP27A1 andcytochrome Cytochrome P450, family 24, subfamily A, polypeptide 1 ( CYP24A1 ) toform a 1-alpha,24,26-trihydroxy-vitamin D2 trihydroxylated metabolite [5], [8] that undergoes subsequent oxidation at C-26 catalyzed byCYP24A1 [8], [9] with1alpha-,24-dihydroxy-26-carboxy-vitamin D2 as a product.

25-OH-vitamin D2 can be further hydroxylated by CYP24A1 when a24,25-Dihydroxyvitamin D2 metabolite is formed [6].

The same P450 enzyme catalyzes all further steps of 1,25-Dihydroxyvitamin D2degradation that include: hydroxylation at C-24 to form 1-alfa-,24-,25-(OH)3-vitaminD2 as a product and subsequent hydroxylation at C-28 to form1-alfa-,24-,25-,28-(OH)4-vitamin D2. The following hydroxyl group migrationresults in production of stereo isomers of which only1-alfa-,24(R)-,25-,26-Tetrahydroxy-Vitamin D2 participates in C-24 hydroxyl groupoxidation to form 1alfa-,25-,26-trihydroxy-24-oxo-vitamin D2 metabolite. Thismetabolite is then hydroxylated to 1alpha-,23-,25-,26-tetrahydroxy-24-oxo-vitaminD2 and undergoes a side-chain degradation to1,23-Dihydroxy-24,25,26,27-tetranorvitamin D3. At the final stage, the lattermetabolite is oxidized to form Calcitroic acid.

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