REGULATION OF KERATINOCYTE GROWTH, DIFFERENTIATION, AND VITAMIN-D METABOLISM BY ANALOGS OF 1,25-DIHYDROXYVITAMIN-D

1,25(OH)2D has numerous actions on many tissues. Analogs of 1,25(OH)2D are being sought that are selective, to further an understanding of t he mechanisms of action of 1,25(OH)2D and to improve its therapeutic e fficacy. Toward these ends we examined eight analogs of 1,25(OH)2D for their ability to regulate 25OHD metabolism by keratinocytes. Choosing the three most potent, we then examined their ability to inhibit kera tinocyte proliferation, stimulate cornified envelope formation (a mark er of differentiation), and bind to the 1,25(OH)2D receptor (VDR). 1,2 5(OH)2-24F2-D, 1,25(OH)2-DELTA16-D, and 1,25(OH)2-DELTA16,23yne-D prov ed the most potent in inhibiting 1,25(OH)2D production and stimulating 24,25(OH)2D production, being approximately 10-100 times more potent than 1,25(OH)2D itself. 1,25(OH)2-DELTA16-D had the highest affinity f or the VDR (fourfold higher than that for that for 1,25(OH)2D itself) and had the greatest ability both to inhibit proliferation and to stim ulate differentiation. 1,25(OH)2-DELTA16,23yne-D also had a higher aff inity for the VDR but was of less or equal potency in stimulating corn ified envelope formation and inhibiting proliferation. 1,25(OH)2-24F2D 2, which was the most potent regulator of 25OHD metabolism, had a lowe r affinity for the VDR and was less potent than 1,25(OH)2D in inhibiti ng proliferation. Our results indicate that even in the same cell diff erent analogs have different rank orders of potency for the various ac tions of 1,25(OH)2D.