title: Alisol B 23-acetate from the rhizomes of Alisma orientale is a natural agonist of the human pregnane X receptor.
abstract: BACKGROUND
  Pregnane X receptor (PXR) is a key regulator of the induction of drug metabolizing enzymes. PXR has been studied for its importance in drug-drug or herb-drug interactions, and it is also a molecular target for the treatment of inflammatory and metabolic diseases.
  
  
  OBJECTIVE
  This study aims to determine new natural PXR-ligands from traditional plant medicines.
  
  
  METHODS
  The PXR activation activity was measured by a mammalian one hybrid assay of PXR. Identification of the active compound from Alisma rhizome (the rhizomes of Alisma orientale) was carried out by bioassay-guided fractionation method. The transcriptional activity of the liver-enriched nuclear receptors was measured by the luciferase reporter assay. The interaction between the SRC-1 and PXR was measured by a mammalian 2-hybrid assay. The expression of endogenous CYP3A4 mRNA in both cultured hPXR-overexpressing hepatoma cells and human primary hepatocytes were measured by quantitative RT-PCR method.
  
  
  RESULTS
  The extract of Alisma rhizome showed the most potent activation activity by screening of a library of medicinal plant extracts. Alisol B 23-acetate (ABA) was identified to be the active compound of Alisma rhizome. ABA caused a concentration-dependent increase on the PXR-dependent transactivation of a luciferase reporter gene, but did not affect the ligand binding activity of the liver-enriched nuclear receptors, such as CAR, LXR, FXR, PPARα, PPARδ and PPARγ, emphasizing that ABA is a potent and specific agonist of PXR. With ABA treatment, the direct interaction between the ligand-binding domain of PXR and the receptor interaction domain of SRC1 was observed. ABA also induced the expression of endogenous CYP3A4 mRNA in both cultured hPXR-overexpressing hepatoma cells and human primary hepatocytes.
  
  
  CONCLUSIONS
  Since the rhizomes of Alisma orientale are used for a wide range of ailments in traditional Chinese medicine and Japanese Kampo medicine, this study could possibly extend into the clinical usage of these medicines via the mechanism of PXR activation.
authors.affiliation: Department of Molecular Toxicology, Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan. Electronic address: ykanno@phar.toho-u.ac.jp.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Kanno
authors.affiliation: Department of Molecular Toxicology, Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan.
authors.forename: Tomofumi
authors.initials: T
authors.lastname: Yatsu
authors.affiliation: Department of Molecular Toxicology, Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Yamashita
authors.affiliation: Department of Molecular Toxicology, Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan.
authors.forename: Shuai
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan. Electronic address: liwei@phar.toho-u.ac.jp.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Imai
authors.affiliation: Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan.
authors.forename: Manami
authors.initials: M
authors.lastname: Kashima
authors.affiliation: Department of Molecular Toxicology, Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Inouye
authors.affiliation: Department of Molecular Toxicology, Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan.
authors.forename: Kiyomitsu
authors.initials: K
authors.lastname: Nemoto
authors.affiliation: Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Koike
mesh_terms: D034902:Alisma / Q000737:chemistry*; D000818:Animals; D002681:China; D002783:Cholestenones / Q000494:pharmacology*; D006801:Humans; D008516:Medicine, Chinese Traditional; D010936:Plant Extracts / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000819:agonists*; D027343:Rhizome / Q000737:chemistry*
chemical_list: D002783:Cholestenones; D010936:Plant Extracts; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid
keywords: Alisma orientale; Alisma rhizome; Alisol B 23-acetate; Nuclear receptor; Pregnane X receptor