ABSTRACT
Retinoic acid constantly undergoes structural inter-conversions among the geometrical isomers (all-trans-retinoic acid, 9-cis-retinoic acid, 11-cis-retinoic acid, 13-cis-retinoic acid and 9-13-di-cis-retinoic acid) by photoisomerization under natural light. Geometric isomers of retinoic acid thus formed showed different effects on human epidermal keratinocyte growth and differentiation. The ability of the isomers to inhibit the synthesis of cornified envelope (terminal event in the keratinocyte differentiation program) changed rapidly when illuminated by white fluorescent light. The 11-cis-retinoic acid had a 3-fold stronger activity to inhibit the growth of keratinocytes than the other geometric isomers. On the other hand, all-trans-retinoic acid, 9-cis-retinoic acid and 9-13-di-cis-retinoic acid exhibited a 3-fold greater ability to inhibit synthesis of involucrin, transglutaminase and the cornified envelopes. The regulation of keratin expression by the geometric isomers of retinoic acids was extremely complex. Level of keratin-1 (K1) mRNA was increased by 11-cis-retinoic acid and 13-cis-retinoic acid, but suppressed by 9,13-di-cis-retinoic acids while all-trans-retinoic acid and 9-cis-retinoic acid had no effect. Level of keratin-10 (K10) mRNA was strongly inhibited by all-trans-retinoic acid, 9-cis-retinoic acid and 11-cis-retinoic acid as compared to 13-cis-retinoic acid and 9,13-di-cis-retinoic acids. The mRNA level of keratin-14 (K14) was suppressed by all-trans-retinoic acid, 9-cis-retinoic acid and 11-cis-retinoic acid but not influenced by 13-cis-retinoic acid and 9,13-di-cis-retinoic acid. Natural light induced structural inter-conversions among the geometric isomers of retinoic acids in tissues-especially the skin, might play a crucial role in the regulation of growth and differentiation of keratinocytes.
Subject(s)
Keratinocytes/drug effects , Tretinoin/chemistry , Tretinoin/pharmacology , Cell Differentiation/drug effects , Cell Division/drug effects , Cells, Cultured , Humans , Keratinocytes/cytology , Keratinocytes/metabolism , Keratins/genetics , Photochemistry , RNA, Messenger/genetics , RNA, Messenger/metabolism , Stereoisomerism , Tretinoin/radiation effectsABSTRACT
Among the series of metabolic analogs of the eccentric cleavage pathway of beta-carotene with different side chain lengths, retinoic acid was shown to have exceedingly higher molecular flexibility to undergo photoisomerization into the geometrical isomers under white fluorescent light. When irradiated with white fluorescent lamps (1,200 lx), the velocity of photoisomerization of all-trans-retinoic acid (8.4 x 10(-7) mol/L.min) was exceedingly higher than those of the other analogs: ionylideneacetic acid (4 x 10(-8) mol/L.min), ionylidenecrotonic acid (3.0 x 10(-7) mol/L.min), all-trans-beta-apo-14'-carotenoic acid (1.7 x 10(-7) mol/L.min), all-trans-beta-apo-12'-carotenoic acid (1.3 x 10(-7) mol/L.min), and all-trans-beta-apo-8'-carotenoic acid (0.1 x 10(-7) mol/L.min). beta-Carotene did not undergo photoisomerization under the experimental conditions. The molecular flexibility of retinoic acid is assumed to be an important basis of the mechanism of action of retinoic acid.
