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.
Araki
H
H
First Department of Internal Medicine, Gifu University School of Medicine, Japan.
Shidoji
Y
Y
Yamada
Y
Y
Moriwaki
H
H
Muto
Y
Y
D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012176:Retinoids / Q000819:agonists* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004224:Diterpenes; D018168:Receptors, Retinoic Acid; D012176:Retinoids; C082928:retinoic acid binding protein II, cellular; C082925:retinoic acid receptor beta; C040155:geranylgeranic acid; D015500:Chloramphenicol O-Acetyltransferase