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

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.