RRC ID 45057
Author Tanabe H, Yasui T, Kotani H, Nagatsu A, Makishima M, Amagaya S, Inoue M.
Title Retinoic acid receptor agonist activity of naturally occurring diterpenes.
Journal Bioorg Med Chem
Abstract Recent accumulating evidence indicates that all-trans retinoic acid (ATRA) may be useful for preventing or treating inflammation, allergy, and autoimmune diseases, despite its severe side effects. In this study, screening of 99 crude drugs for retinoic acid receptor (RAR) ligands by luciferase reporter assay demonstrated that the methanol extract of Aralia cordata Rhizoma most effectively activates the transcriptional activity of RARα. Pimaradienoic acid (ent-pimara-8(14),15-dien-19-oic acid) was subsequently isolated as the constituent capable of activating RAR. Pimaric acid and abietic acid, which have similar structures to pimaradienoic acid, were also found to be novel RAR agonists, although abietic acid only slightly activated peroxisome proliferator-activated receptor gamma. These three natural RAR agonists with diterpene structures, while structurally different from ATRA, were able to increase the mRNA levels of the constitutive androstane receptor in HepG2 cells, induce F9 cell differentiation followed by Cyp26a1 mRNA expression, and differentiate HL-60 cells via RAR activation in a different manner from ATRA. These results demonstrate that some diterpenes exist as naturally occurring RAR agonists and that the differences in chemical structure between ATRA and these diterpenes may induce distinct gene activation and a specific cellular response.
Volume 22(12)
Pages 3204-12
Published 2014-6-15
DOI 10.1016/j.bmc.2014.03.047
PII S0968-0896(14)00243-0
PMID 24799257
MeSH Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology Aralia / chemistry* Cell Differentiation / drug effects Cell Proliferation / drug effects* Cells, Cultured Constitutive Androstane Receptor Cytochrome P-450 Enzyme System / genetics Cytochrome P-450 Enzyme System / metabolism Diterpenes / chemistry Diterpenes / pharmacology* HL-60 Cells Humans Plant Extracts / pharmacology* RNA, Messenger / genetics Real-Time Polymerase Chain Reaction Receptors, Cytoplasmic and Nuclear / genetics Receptors, Cytoplasmic and Nuclear / metabolism Receptors, Retinoic Acid / agonists* Retinoic Acid 4-Hydroxylase Reverse Transcriptase Polymerase Chain Reaction Rhizome / chemistry* Transcription, Genetic Tretinoin / chemistry Tretinoin / pharmacology
IF 3.073
Times Cited 8
Human and Animal Cells 293(RCB1637)