title: Anti-proliferative activity and target cell catabolism of the vitamin D analog 1 alpha,24(S)-(OH)2D2 in normal and immortalized human epidermal cells.
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, 1 alpha,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 1 alpha,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 1 alpha,25-dihydroxyvitamin D3. Furthermore, 1 alpha,24(S)-dihydroxyvitamin D2 was metabolized by the human keratinocyte cell line HPK1A-ras at a slower rate than either 1 alpha,25-dihydroxyvitamin D3 or calcipotriol, a drug used effectively in the treatment of psoriasis. We characterized the metabolic products of 1 alpha,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 1 alpha,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 1 alpha,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.
authors.affiliation: Department of Biochemistry, Queen's University, Kingston, on, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Jones
authors.forename: V
authors.initials: V
authors.lastname: Byford
authors.forename: H L
authors.initials: HL
authors.lastname: Makin
authors.forename: R
authors.initials: R
authors.lastname: Kremer
authors.forename: R H
authors.initials: RH
authors.lastname: Rice
authors.forename: L A
authors.initials: LA
authors.lastname: deGraffenried
authors.forename: J C
authors.initials: JC
authors.lastname: Knutson
authors.forename: C W
authors.initials: CW
authors.lastname: Bishop
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002461:Cell Line, Transformed; D002851:Chromatography, High Pressure Liquid; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects*; D004872:Ergocalciferols / Q000378:metabolism / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice
chemical_list: D004872:Ergocalciferols; C063087:1,24-dihydroxyvitamin D2