期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 279, 期 16, 页码 15897-15907出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M311473200
关键词
-
Recently, it was revealed that 1alpha, 25-dihydroxyvitamin D-3 (1alpha,25(OH)(2)D-3) and24R,25-dihydroxyvitamin D-3 (24,25 (OH)(2)D-3) 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 D-3 (3-epi-25(OH)D-3) as a major metabolite of 25-hydroxyvitamin D-3 (25(OH)D-3) and the further metabolism of C-3 epimers of vitamin D-3 metabolites. When 25(OH) D3 was incubated with various cultured cells including osteosarcoma, colon adenocarcinoma, and hepatoblastoma cell lines, 3-epi-25(OH)D-3 and 24,25 (OH)(2)D-3 were commonly observed as a major and minor metabolite of 25(OH)D-3, respectively. 25(OH)D-3 was at least as sensitive to C-3 epimerization as 1alpha,25(OH)(2)D-3 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)(2)D-3 rather than 3-epi-25(OH)D-3. We also confirmed the existence of 3-epi-25(OH)D-3 in the serum of rats intravenously given pharmacological doses of 25(OH)D-3. The cultured cells metabolized 3-epi-25(OH)D-3 and 3-epi-1alpha,25(OH)(2)D-3 to 3-epi-24,25(OH)(2)D-3 and 3-epi-1alpha,24,25(OH)(3)D-3, respectively. In addition, we demonstrated that 3-epi-25(OH)D-3 was metabolized to 3-epi-1alpha,25(OH)(2)D-3 by CYP27B1 and to 3-epi-24,25(OH)(2)D-3 by CYP24 using recombinant Escherichia coli cell systems. 3-Epi-25(OH)D-3, 3-epi-1alpha,25(OH)(2)D-3, and 3-epi-24,25(OH)(2)D-3 were biologically less active than 25(OH)D-3, 1alpha,25(OH)(2)D-3, and 24,25(OH)(2)D-3, but 3-epi-1alpha,25(OH)(2)D-3 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 D-3.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据