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BIBTEX RIS

Evidence for the activation of 1α-hydroxyvitamin D2 by 25-hydroxyvitamin D-24-hydroxylase: Delineation of pathways involving 1α,24-dihydroxyvitamin D2 and 1α,25-dihydroxyvitamin D2

2006; Elsevier BV; Volume: 1761; Issue: 2 Linguagem: Inglês

10.1016/j.bbalip.2006.01.004

ISSN

1879-2618

Autores

Sonoko Masuda, Stephen A. Strugnell, Joyce C. Knutson, René St‐Arnaud, Glenville Jones,

Tópico(s)

Adrenal Hormones and Disorders

Resumo

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, 1α-hydroxyvitamin D2 (1α(OH)D2) in vitro. Mammalian cells stably transfected with CYP24A1 (V79-CYP24A1) converted 1α(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 1α(OH)D2 included the active metabolites 1α,24-dihydroxyvitamin D2 (1α,24(OH)2D2) and 1α,25-dihydroxyvitamin D2 (1α,25(OH)2D2); the formation of both indicating the existence of distinct activation pathways. A novel water-soluble metabolite, identified as 26-carboxy-1α,24(OH)2D2, was the presumed terminal degradation product of 1α(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 1α(OH)D2 and 1α,24(OH)2D2 relative to 1α,25(OH)2D2 and 1α,25(OH)2D3 were noted, arguing for a role of 24-hydroxylated metabolites in the altered biological activity profile of 1α(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.

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