title: Valerian inhibits rat hepatocarcinogenesis by activating GABA(A) receptor-mediated signaling.
abstract: Valerian is widely used as a traditional medicine to improve the quality of sleep due to interaction of several active components with the γ-aminobutyric acid (GABA) A receptor (GABA(A)R) system. Recently, activation of GABA signaling in stem cells has been reported to suppress cell cycle progression in vivo. Furthermore, possible inhibitory effects of GABA(A)R agonists on hepatocarcinogenesis have been reported. The present study was performed to investigate modulating effects of Valerian on hepatocarcinogenesis using a medium-term rat liver bioassay. Male F344 rats were treated with one of the most powerful Valerian species (Valeriana sitchensis) at doses of 0, 50, 500 and 5000 ppm in their drinking water after initiation of hepatocarcinogenesis with diethylnitrosamine (DEN). Formation of glutathione S-transferase placental form positive (GST-P(+)) foci was significantly inhibited by Valerian at all applied doses compared with DEN initiation control rats. Generation of 8-hydroxy-2'-deoxyguanosine in the rat liver was significantly suppressed by all doses of Valerian, likely due to suppression of Nrf2, CYP7A1 and induction of catalase expression. Cell proliferation was significantly inhibited, while apoptosis was induced in areas of GST-P(+) foci of Valerian groups associated with suppression of c-myc, Mafb, cyclin D1 and induction of p21(Waf1/Cip1), p53 and Bax mRNA expression. Interestingly, expression of the GABA(A)R alpha 1 subunit was observed in GST-P(+) foci of DEN control rats, with significant elevation associated with Valerian treatment. These results indicate that Valerian exhibits inhibitory effects on rat hepatocarcinogenesis by inhibiting oxidative DNA damage, suppressing cell proliferation and inducing apoptosis in GST-P(+) foci by activating GABA(A)R-mediated signaling.
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Anna
authors.initials: A
authors.lastname: Kakehashi
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kato
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Keiichirou
authors.initials: K
authors.lastname: Morimura
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Fukushima
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Wanibuchi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004052:Diethylnitrosamine; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010936:Plant Extracts / Q000494:pharmacology*; D018517:Plant Roots / Q000737:chemistry; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D011916:Rats, Inbred F344; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D014632:Valerian / Q000737:chemistry*
chemical_list: D010936:Plant Extracts; D018809:Proliferating Cell Nuclear Antigen; D011963:Receptors, GABA-A; D004052:Diethylnitrosamine; D051549:Glutathione S-Transferase pi; C496558:Gstp1 protein, rat