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.
From: Department of Biochemistry, Queen’s University, Kingston, Ontario, Canada K7L 3N6.
Biochimica et biophysica acta
- Publish Date: Feb 2006
- ISSN: 0006-3002
- Volume: 1761
- Issue: 2
- Pages: 221-34
- Medium: Print
- Language: English
- Citation (JAMA): Masuda Sonoko, Strugnell Stephen A, Knutson Joyce C, et al. 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.. Biochim. Biophys. Acta Feb 2006;1761:221-34
Abstract
While current dogma argues that vitamin D prodrugs require side-chain activation by liver enzymes, recent data suggest that hydroxylation may also occur extrahepatically. We used keratinocytes and recombinant human enzyme to test if the 25-hydroxyvitamin D-24-hydroxylase (CYP24A1) is capable of target cell activation and inactivation of a model prodrug, 1alpha-hydroxyvitamin D2 (1alpha(OH)D2) in vitro. Mammalian cells stably transfected with CYP24A1 (V79-CYP24A1) converted 1alpha(OH)D2 to a series of metabolites similar to those observed in murine keratinocytes and the human cell line HPK1A-ras, confirming the central role of CYP24A1 in metabolism. Products of 1alpha(OH)D2 included the active metabolites 1alpha,24-dihydroxyvitamin D2 (1alpha,24(OH)2D2) and 1alpha,25-dihydroxyvitamin D2 (1alpha,25(OH)2D2); the formation of both indicating the existence of distinct activation pathways. A novel water-soluble metabolite, identified as 26-carboxy-1alpha,24(OH)2D2, was the presumed terminal degradation product of 1alpha(OH)D2 synthesized by CYP24A1 via successive 24-hydroxylation, 26-hydroxylation and further oxidation at C-26. This acid was absent in keratinocytes from Cyp24a1 null mice. Slower clearance rates of 1alpha(OH)D2 and 1alpha,24(OH)2D2 relative to 1alpha,25(OH)2D2 and 1alpha,25(OH)2D3 were noted, arguing for a role of 24-hydroxylated metabolites in the altered biological activity profile of 1alpha(OH)D2. Our findings suggest that CYP24A1 can activate and inactivate vitamin D prodrugs in skin and other target cells in vitro, offering the potential for treatment of hyperproliferative disorders such as psoriasis by topical administration of these prodrugs.
Mesh Headings (Keywords): Animals, Cell Line, Ergocalciferols, Humans, Hydroxylation, Keratinocytes, Mice, Mice, Knockout, Models, Biological, Prodrugs, Recombinant Proteins, Solubility, Steroid Hydroxylases, Transfection, Water
Check for Full Text / PubMed Unique Identifier (PMID): 16516540
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