Pathway maps

Vitamin D2 (ergocalciferol) metabolism
Vitamin D2 (ergocalciferol) metabolism

Object List (links open in MetaCore):

1-alpha,24,26-trihydroxy-vitamin D2, 1.14.13.- 1.14.14.-, 25-OH- vitamin D2, 1.14.-.-, 24-OH- vitamin D2, Vitamin D2, 1alpha-,24-dihydroxy-26-carboxy-vitamin D2, 1.14.-.-, 1.14.-.-, 1,25-Dihydroxyvitamin D2, 1.14.-.-, CYP3A4, 1alfa-,25-,26-trihydroxy-24-oxo-vitamin D2, 1.14.-.-, CYP27A1, 24-OH- vitamin D2, 1.14.-.-, CYP2R1, 1.14.-.-, 1.14.-.-, 1,24-Dihydroxyvitamin D2, 24,25-Dihydroxyvitamin D2, 1.14.-.-, 1-alfa-,24(R)-,25-,26-Tetrahydroxy-Vitamin D2, 1.14.-.-, 1alpha-,23-,25-,26-tetrahydroxy-24-oxo-vitamin D2, 1-alfa-,24-,25-,28-(OH)4-vitamin D2, 1,25-Dihydroxyvitamin D2, CYP2C9, 1.14.-.-, 1.14.13.- 1.14.14.-, 25-OH- vitamin D2, 1,24-Dihydroxyvitamin D2, 1.14.-.-, CYP27B1, Calcitroic acid, 1-alfa-,24-,25-(OH)3-vitamin D2, CYP24A1, 1.14.-.-, 1,23-Dihydroxy-24,25,26,27- tetranorvitamin D3, Doxercalciferol, 1.14.-.-


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.


  1. Gupta RP, Hollis BW, Patel SB, Patrick KS, Bell NH
    CYP3A4 is a human microsomal vitamin D 25-hydroxylase. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2004 Apr;19(4):680-8
  2. Gupta RP, He YA, Patrick KS, Halpert JR, Bell NH
    CYP3A4 is a vitamin D-24- and 25-hydroxylase: analysis of structure function by site-directed mutagenesis. The Journal of clinical endocrinology and metabolism 2005 Feb;90(2):1210-9
  3. Knutson JC, Hollis BW, LeVan LW, Valliere C, Gould KG, Bishop CW
    Metabolism of 1 alpha-hydroxyvitamin D2 to activated dihydroxyvitamin D 2 metabolites decreases endogenous 1 alpha, 25-dihydroxyvitamin D 3 in rats and monkeys. Endocrinology 1995 Nov;136(11):4749-53
  4. Strugnell S, Byford V, Makin HL, Moriarty RM, Gilardi R, LeVan LW, Knutson JC, Bishop CW, Jones G
    1 alpha,24(S)-dihydroxyvitamin D2: a biologically active product of 1 alpha-hydroxyvitamin D2 made in the human hepatoma, Hep3B. The Biochemical journal 1995 Aug 15;310 ( Pt 1):233-41
  5. Guo YD, Strugnell S, Back DW, Jones G
    Transfected human liver cytochrome P-450 hydroxylates vitamin D analogs at different side-chain positions. Proceedings of the National Academy of Sciences of the United States of America 1993 Sep 15;90(18):8668-72
  6. Mawer EB, Jones G, Davies M, Still PE, Byford V, Schroeder NJ, Makin HL, Bishop CW, Knutson JC
    Unique 24-hydroxylated metabolites represent a significant pathway of metabolism of vitamin D2 in humans: 24-hydroxyvitamin D2 and 1,24-dihydroxyvitamin D2 detectable in human serum. The Journal of clinical endocrinology and metabolism 1998 Jun;83(6):2156-66
  7. Cheng JB, Motola DL, Mangelsdorf DJ, Russell DW
    De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase. The Journal of biological chemistry 2003 Sep 26;278(39):38084-93
  8. Zimmerman DR, Reinhardt TA, Kremer R, Beitz DC, Reddy GS, Horst RL
    Calcitroic acid is a major catabolic metabolite in the metabolism of 1 alpha-dihydroxyvitamin D(2). Archives of biochemistry and biophysics 2001 Aug 1;392(1):14-22
  9. Masuda S, Strugnell SA, Knutson JC, St-Arnaud R, Jones G
    Evidence for the activation of 1alpha-hydroxyvitamin D2 by 25-hydroxyvitamin D-24-hydroxylase: delineation of pathways involving 1alpha,24-dihydroxyvitamin D2 and 1alpha,25-dihydroxyvitamin D2. Biochimica et biophysica acta 2006 Feb;1761(2):221-34