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 n atural hormone, 1 alpha,25-dihydroxyvitamin D-3 (1 alpha,25(OH)(2)D-3) We have previously shown that after topical application in hairless m ice both KH 1060 and 1 alpha,25(OH)(2)D-3 cause epidermal hyperprolife ration. 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 M C 1582 strongly stimulates epidermal hyperplasia in hairless mice afte r topical application in vivo, approaching in potency KH 1060. A simil ar, although much weaker response was also obtained with I alpha-hydro xyvitamin D-3 (1 alpha(OH)D-3). Since only the vitamin D compounds whi ch possess hydroxyl groups both in the position 1 alpha and in the sid e chain, bind to the vitamin D receptor, we suggest that a local metab olism of MC 1582 and 1 alpha(OH)D-3 takes place in the skin to the act ive, side-chain-hydroxylated species, probably to KH 1060 and 1 alpha, 25(OH)(2)D-3. This study suggests that 1 alpha hydroxylated prodrugs m ay be of use in the dermatological treatment of the future.