title: Rheinanthrone, a metabolite of sennoside A, triggers macrophage activation to decrease aquaporin-3 expression in the colon, causing the laxative effect of rhubarb extract.
abstract: BACKGROUND
  Aquaporin-3 (AQP3) is expressed in mucosal epithelial cells in the colon and is important for regulating fecal water content. We examined the role of AQP3 in the laxative effect of rhubarb extract.
  
  
  METHODS
  After orally administering rhubarb extract or its major component (sennoside A) to rats, the fecal water content, AQP3 expression and prostaglandin E2 (PGE2) concentrations in the colon were examined. The mechanism by which sennoside A decreases the expression of AQP3 was examined using the human colon cancer HT-29 cells and macrophage-derived Raw264.7 cells.
  
  
  RESULTS
  During diarrhea by rhubarb extract administration, the PGE2 levels in the colon increased while the AQP3 expression significantly decreased. Similar changes were also observed when sennoside A was administered. When sennoside A or its metabolites, rheinanthrone and rhein were added to Raw264.7 cells, a significant increase in the PGE2 concentration was observed only in cells treated with rheinanthrone. Fifteen minutes after adding PGE2 to the HT-29 cells, the AQP3 expression decreased to approximately 40% of the control. When pretreated with indomethacin, sennoside A neither decreased the AQP3 expression nor induced diarrhea.
  
  
  CONCLUSIONS
  Sennoside A may decrease AQP3 expression in the colon to inhibit water transport from the luminal to the vascular side, leading to a laxative effect. The decreases in the levels of AQP3 are caused by rheinanthrone, which is a metabolite of sennoside A, this metabolite activates the macrophages in the colon and increases the secretion of PGE2; PGE2 acts as a paracrine factor and decreases AQP3 expression in colon mucosal epithelial cells.
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Risako
authors.initials: R
authors.lastname: Kon
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Nobutomo
authors.initials: N
authors.lastname: Ikarashi
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Chika
authors.initials: C
authors.lastname: Nagoya
authors.affiliation: Synthetic Medicinal Chemistry, Hoshi University, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takayama
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kusunoki
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishii
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Ueda
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Ochiai
authors.affiliation: Division of Applied Pharmaceutical Education and Research, Hoshi University, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Machida
authors.affiliation: Synthetic Medicinal Chemistry, Hoshi University, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugita
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. Electronic address: sugiyama@hoshi.ac.jp.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Sugiyama
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000302:isolation & purification / Q000494:pharmacology; D051400:Aquaporin 3 / Q000378:metabolism*; D002460:Cell Line; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced; D015232:Dinoprostone / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D054368:Laxatives / Q000302:isolation & purification / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012250:Rheum / Q000737:chemistry*; D012676:Senna Extract / Q000302:isolation & purification / Q000494:pharmacology*; D000081226:Sennosides; D000095322:Anthrones
chemical_list: D000873:Anthracenes; D051400:Aquaporin 3; D015232:Dinoprostone; D007213:Indomethacin; D054368:Laxatives; D012676:Senna Extract; D000081226:Sennosides; C055876:rhein-9-anthrone; D000095322:Anthrones
keywords: Aquaporin-3; Laxative; Macrophage; PGE(2); Rheinanthrone; Sennoside A