Evidence for the activation of vitamin D compounds in the skin by side-chain hydroxylation.

KH 1060 is the 20-epi-22-oxa-24a-homo-26,27-dimethyl analogue of the natural hormone, 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)2D3). We have previously shown that after topical application in hairless mice both KH 1060 and 1 alpha,25(OH)2D3 cause epidermal hyperproliferation. MC 1582 differs from KH 1060 by the lack of hydroxyl group in the side chain which is required for receptor binding. We found that MC 1582 strongly stimulates epidermal hyperplasia in hairless mice after topical application in vivo, approaching in potency KH 1060. A similar, although much weaker response was also obtained with 1 alpha-hydroxyvitamin D3 (1 alpha(OH)D3). Since only the vitamin D compounds which possess hydroxyl groups both in the position 1 alpha and in the side chain, bind to the vitamin D receptor, we suggest that a local metabolism of MC 1582 and 1 alpha(OH)D3 takes place in the skin to the active, side-chain-hydroxylated species, probably to KH 1060 and 1 alpha,25(OH)2D3. This study suggests that 1 alpha hydroxylated prodrugs may be of use in the dermatological treatment of the future.