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C-3 Epimerization of Vitamin D3 Metabolites and Further Metabolism of C-3 Epimers: 25-hydroxyvitamin D3 Is Metabolized to 3-epi-25-hydroxyvitamin D3 and Subsequently Metabolized Through C-1alpha or C-24 Hydroxylation

C-3 Epimerization of Vitamin D3 Metabolites and Further Metabolism of C-3 Epimers: 25-hydroxyvitamin D3 Is Metabolized to 3-epi-25-hydroxyvitamin D3 and Subsequently Metabolized Through C-1alpha or C-24 Hydroxylation

Maya Kamao, Syuichiro Tatematsu, Susumi Hatakeyama, Toshiyuki Sakaki, Natsumi Sawada, Kuniyo Inouye, Keiichi Ozono, Noboru Kubodera, G Satyanarayana Reddy, Toshio Okano

J Biol Chem. 2004 Apr 16;279(16):15897-907.

PMID: 14757768

Abstract:

Recently, it was revealed that 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) and 24R,25-dihydroxyvitamin D3 (24,25(OH)2D3) were metabolized to their respective epimers of the hydroxyl group at C-3 of the A-ring. We now report the isolation and structural assignment of 3-epi-25-hydroxyvitamin D3 (3-epi-25(OH)D3 as a major metabolite of 25-hydroxyvitamin D3 (25(OH)D3) and the further metabolism of C-3 epimers of vitamin D3 metabolites. When 25(OH)D3 was incubated with various cultured cells including osteosarcoma, colon adenocarcinoma, and hepatoblastoma cell lines, 3-epi-25(OH)D3 and 24,25 (OH)2D3 were commonly observed as a major and minor metabolite of 25(OH)D3, respectively. 25(OH)D3 was at least as sensitive to C-3 epimerization as 1alpha, 25(OH)2D3 which has been reported as a substrate for the C-3 epimerization reaction. Unlike these cultured cells, LLC-PK1 cells, a porcine kidney cell line, preferentially produced 24,25(OH)2D3 rather than 3-epi-25(OH)D3. We also confirmed the existence of 3-epi-25(OH)D3 in the serum of rats intravenously given pharmacological doses of 25(OH)D3. The cultured cells metabolized 3-epi-25OHD3 and 3-epi-1alpha,25(OH)2D3 to 3-epi-24,25(OH)2D3 and 3-epi-1alpha,24,25(OH)3D3, respectively. In addition, we demonstrated that 3-epi-25(OH)D3 was metabolized to 3-epi-1alpha,25(OH)2D3 by CYP27B1 and to 3-epi-24,25(OH)2D3 by CYP24 using recombinant Escherichia coli cell systems. 3-Epi-25(OH)D3, 3-epi-1alpha,25(OH)2D3, and 3-epi-24,25(OH)2D3 were biologically less active than 25(OH)D3, 1alpha,25(OH)2D3, and 24,25(OH)2D3, but 3-epi-1alpha,25(OH)2D3 showed to some extent transcriptional activity toward target genes and anti-proliferative/differentiation-inducing activity against human myeloid leukemia cells (HL-60). These results indicate that C-3 epimerization may be a common metabolic pathway for the major metabolites of vitamin D3.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP73809059-A	3-epi-25-Hydroxyvitamin D3		73809-05-9	Price

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