Rheinanthrone, a metabolite of sennoside A, triggers macrophage activation to decrease aquaporin-3 expression in the colon, causing the laxative effect of rhubarb extract

Ethnopharmacological relevance: 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 E-2 (PGE(2)) 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 PGE(2) 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 PGE(2) concentration was observed only in cells treated with rheinanthrone. Fifteen minutes after adding PGE(2) 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 PGE(2); PGE(2) acts as a paracrine factor and decreases AQP3 expression in colon mucosal epithelial cells. (C) 2014 Elsevier Ireland Ltd. All rights reserved.