Anti-proliferative activity and target cell catabolism of the vitamin D analog 1α,24(S)-(OH)2D2 in normal and immortalized human epidermal cells

Glenville Jones, Valarie Byford, Hugh L J Makin, Richard Kremer, Robert H. Rice, Lea Ann DeGraffenried, Joyce C. Knutson, Charles W. Bishop

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Vitamin D analogs represent valuable new agents for the suppression of proliferation of a variety of cell types, including those of the skin. One such analog is the vitamin D2 metabolite, 1α,24(S)-dihydroxyvitamin D2, which binds strongly to the vitamin D receptor and induces vitamin D-dependent gene expression in vitro. In the work described here, we studied the anti-proliferative activity and target cell metabolism of 1α,24(S)-dihydroxyvitamin D2 in cells of human epidermal origin. We found this analog to be equally potent in its anti-proliferative effect to the hormone 1α,25-dihydroxyvitamin D3. Furthermore, 1α,24(S)-dihydroxyvitamin D2 was metabolized by the human keratinocyte cell line HPK1A-ras at a slower rate than either 1α,25-dihydroxyvitamin D3 or calcipotriol, a drug used effectively in the treatment of psoriasis. We characterized the metabolic products of 1α,24(S)-dihydroxyvitamin D2 as a mixture of side-chain truncated and hydroxylated products. The main product was identified by GC-MS and NMR techniques as 1α,24(S),26-trihydroxyvitamin D2. The biological activity of this main product was determined in a vitamin D-dependent, growth-hormone reporter gene expression system to be lower than that of the parent molecule. We conclude from these data that 1α,24(S)-dihydroxyvitamin D2 is a valuable new anti-proliferative agent with a slower rate of catabolism by cells of epidermal origin. Preliminary evidence suggests that the parent molecule, and not its products, is responsible for this biological activity in vitro.

Original languageEnglish (US)
Pages (from-to)133-140
Number of pages8
JournalBiochemical Pharmacology
Volume52
Issue number1
DOIs
StatePublished - Jul 12 1996

Keywords

  • 1α,24(S)-dihydroxyvitamin D
  • 1α,25-dihydroxyvitamin D
  • anti-proliferative activity
  • GC-MS
  • HPK1A-ras
  • human epidermal cells
  • human keratinocyte
  • NMR
  • vitamin D analogs

ASJC Scopus subject areas

  • Pharmacology

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    Jones, G., Byford, V., Makin, H. L. J., Kremer, R., Rice, R. H., DeGraffenried, L. A., Knutson, J. C., & Bishop, C. W. (1996). Anti-proliferative activity and target cell catabolism of the vitamin D analog 1α,24(S)-(OH)2D2 in normal and immortalized human epidermal cells. Biochemical Pharmacology, 52(1), 133-140. https://doi.org/10.1016/0006-2952(96)00173-6