Anti-proliferative activity and target cell catabolism of the vitamin D analog 1α,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 D 2 metabolite, 1 α ,24( S )-dihydroxyvitamin D 2 , 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 α ,24( S )-dihydroxyvitamin D 2 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 D 3 . Furthermore, 1 α ,24( S )-dihydroxyvitamin D 2 was metabolized by the human keratinocyte cell line HPK1A- ras at a slower rate than either 1α,25-dihydroxyvitamin D 3 or calcipotriol, a drug used effectively in the treatment of psoriasis. We characterized the metabolic products of 1 α ,24( S )-dihydroxyvitamin D 2 as a mixture of side-chain truncated and hydroxylated products. The main product was identified by GC-MS and NMR techniques as 1 α ,24( S ),26-trihydroxyvitamin D 2 . 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 α ,24( S )-dihydroxyvitamin D 2 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 .