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 language | English (US) |
|---|---|
| Pages (from-to) | 133-140 |
| Number of pages | 8 |
| Journal | Biochemical Pharmacology |
| Volume | 52 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 12 1996 |
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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
Cite this
Anti-proliferative activity and target cell catabolism of the vitamin D analog 1α,24(S)-(OH)2D2 in normal and immortalized human epidermal cells. / Jones, Glenville; Byford, Valarie; Makin, Hugh L J; Kremer, Richard; Rice, Robert H.; DeGraffenried, Lea Ann; Knutson, Joyce C.; Bishop, Charles W.
In: Biochemical Pharmacology, Vol. 52, No. 1, 12.07.1996, p. 133-140.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Anti-proliferative activity and target cell catabolism of the vitamin D analog 1α,24(S)-(OH)2D2 in normal and immortalized human epidermal cells
AU - Jones, Glenville
AU - Byford, Valarie
AU - Makin, Hugh L J
AU - Kremer, Richard
AU - Rice, Robert H.
AU - DeGraffenried, Lea Ann
AU - Knutson, Joyce C.
AU - Bishop, Charles W.
PY - 1996/7/12
Y1 - 1996/7/12
N2 - 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.
AB - 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.
KW - 1α,24(S)-dihydroxyvitamin D
KW - 1α,25-dihydroxyvitamin D
KW - anti-proliferative activity
KW - GC-MS
KW - HPK1A-ras
KW - human epidermal cells
KW - human keratinocyte
KW - NMR
KW - vitamin D analogs
UR - http://www.scopus.com/inward/record.url?scp=0030008637&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030008637&partnerID=8YFLogxK
U2 - 10.1016/0006-2952(96)00173-6
DO - 10.1016/0006-2952(96)00173-6
M3 - Article
C2 - 8678897
AN - SCOPUS:0030008637
VL - 52
SP - 133
EP - 140
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 1
ER -