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.
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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.
Biochim Biophys Acta. 2006 Feb;1761(2):221-34. Epub 2006 Feb 2.
- PubMed ID
- 16516540 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Ergocalciferol 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial Protein Humans NoSubstrateDetails Ergocalciferol Sterol 26-hydroxylase, mitochondrial Protein Humans UnknownSubstrateDetails Ergocalciferol Vitamin D 25-hydroxylase Protein Humans NoSubstrateDetails