RETINOIC ACID ISOMERS APPLIED TO HUMAN SKIN IN-VIVO EACH INDUCE A 4-HYDROXYLASE THAT INACTIVATES ONLY TRANS RETINOIC ACID

Application of all-trans retinoic acid to human skin for 4 d under occ lusion produces a marked increase in retinoic acid 4-hydroxylase activ ity. In this study, the possible induction of other hydroxylases in re sponse to 9-cis and 13-cis retinoic acid applications to adult human s kin in vivo was determined. Application of 0.1% all-trans, 0.1% 9-cis, and 0.1% 13-cis retinoic acid to human skin for 2 d resulted in induc tion of only all-trans retinoic acid 4-hydroxylase activity. The 4-hyd roxylase activity in microsomes from the treated tissue ranged from 38 3 +/- 46 to 531 +/- 59 pg of 4-hydroxy all-trans retinoic acid formed/ min/mg protein (n = 6). These same preparations were unable to use 9-c is or 13-cis retinoic acid as substrate for the hydroxylation reaction . Extraction of the retinoic acid isomers from epidermis 48 h after ap plication of 0.1% solution of each isomer yielded significant amounts of all-trans retinoic acid (36-72%) regardless of the isomer applied. The all-trans isomer produced by isomerization of both 9-cis and 13-ci s retinoic acids is the likely inducer of the 4-hydroxylase. All-trans retinol and all-trans retinal were unable to compete with all-trans r etinoic acid as substrate for 4-hydroxylase enzyme. The 4-hydroxylase induced in response to pharmacological doses of retinoic acids is spec ific for the all-trans isomer. The inability of 9-cis or 13-cis retino ic acid to induce their own hydroxylation and inactivation or act as s ubstrate for the 4-hydroxylase in skin may have considerable implicati ons in light of the clinical use of retinoids in the treatment of vari ous diseases including cancers.