title: Retinoic acid receptor agonist activity of naturally occurring diterpenes.
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.
authors.affiliation: Laboratory of Medicinal Resources, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tanabe
authors.affiliation: Laboratory of Medicinal Resources, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yasui
authors.affiliation: Laboratory of Medicinal Resources, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan; Department of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo, Tokyo 202-8585, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kotani
authors.affiliation: Laboratory of Pharmacognosy, Kinjo Gakuin University, 2-1723 Omori, Moriyama-ku, Nagoya 463-8521, Japan.
authors.forename: Akito
authors.initials: A
authors.lastname: Nagatsu
authors.affiliation: Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8619, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.affiliation: Department of Kampo Pharmaceutical Sciences, Nihon Pharmaceutical University, 10281 Komuro, Ina-machi, Kita-adachi-gun, Saitama 362-0800, Japan.
authors.forename: Sakae
authors.initials: S
authors.lastname: Amagaya
authors.affiliation: Laboratory of Medicinal Resources, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan. Electronic address: minoue@dpc.aichi-gakuin.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D027983:Aralia / Q000737:chemistry*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D010936:Plant Extracts / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D000072516:Retinoic Acid 4-Hydroxylase; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027343:Rhizome / Q000737:chemistry*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D000090702:Constitutive Androstane Receptor; D004224:Diterpenes; D010936:Plant Extracts; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; C008911:pimaric acid; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase
keywords: Abietic acid; Aralia cordata Rhizoma; Pimaradienoic acid; Pimaric acid; Retinoic acid receptor