RETINOID AGONIST ACTIVITIES OF SYNTHETIC GERANYL GERANOIC ACID-DERIVATIVES

Micromolar concentrations of 4,5-didehydro geranyl geranoic acid (GGA) were able to induce up-regulation of retinoic acid receptor-beta gene expression in human hepatoma-derived cell line, HuH-7, to the same extent as all-trans RA. In chloramphenicol acetyl transferase (CAT) assay with retinoic acid response element-beta, GGA and 4,5-didehydro GGA were both positive, but 2,3-dihydro GGA was negative, even though these GGA derivatives have been reported to be all potent ligands for cellular retinoic-acid-binding protein(CRABP). However, 10,11,14,15-tetrahydro-4,5-didehydro GGA, a compound without any affinity for CRABP, transactivated CAT gene expression. On the other hand, only GGA and 4,5-didehydro GGA were active to induce CAT gene expression through retinoid X response element of cellular retinol binding protein, type II gene. We show for the first time that chemically synthesized acyclic organic acids are potential agonists of natural retinoids. (C) 1995 Academic Press, Inc.