Herbal components of Japanese Kampo medicines exert laxative actions in colonic epithelium cells via activation of BK and CFTR channels

Tomohiro Numata,Kaori Sato-Numata,Yasunobu Okada

doi:10.1038/s41598-019-52171-z

Abstract

Japanese Kampo medicines Junchoto and Mashiningan are mixtures of numerous herbal plant extracts and empirically known to exert laxative actions by stimulating fluid secretion in the colonic epithelium. However, it is unknown which and how the herbal components of these crude Kampo drugs are effective to stimulate ion effluxes causing fluid secretion. Here, we selected four herbal components of Junchoto and Mashiningan, Mashinin (MSN), Kyonin (KYN), Tonin (TON), and Daio (DIO), which are putatively laxatives, and examined their effects on the ion channel activity of human colonic epithelial Caco-2 cells. Patch clamp analyses revealed that MSN activated whole-cell current characteristics of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, whereas KYN, TON, and DIO activated the large-conductance and voltage-activated K+ (BK) channel. Furthermore, electronic cell sizing showed that MSN induced secretory volume decrease (SVD) sensitivity to a CFTR blocker, whereas TON, KYN, and DIO induced SVD sensitivity to a K+ channel blocker. In conclusion, MSN and TON, KYN, and DIO promote fluid secretion from colonic epithelial cells by activating CFTR and BK channels. Thus, Japanese Kampo medicines, Junchoto and Mashiningan, exert anti-constipation actions by inducing KCl efflux through the combined actions of CFTR- and BK-stimulating herbal components.

Highlights

Chronic constipation is an extremely common gastrointestinal disorder that severely affects quality of life
Solute secretion from cells drives the transfer of osmotically obliged water, resulting in a cell volume reduction, which is called a secretory volume decrease (SVD)[10,11]
We investigated herbal components in two types of Japanese Kampo medicines, JCT and MSG, which are widely used as laxatives, by measuring the SVD in human colonic epithelial Caco-2 cells

Summary

Introduction

Chronic constipation is an extremely common gastrointestinal disorder that severely affects quality of life. Osmotic laxatives contain non-absorbable molecules that drive water from the intestinal epithelium. Secretagogue laxatives induce electrolyte secretion across the intestinal epithelium, driving intestinal fluid secretion. Traditional Japanese Kampo medicines Junchoto (JCT) and Mashiningan (MSG) have been recently shown to induce cAMP production in the intestinal epithelium and activate CFTR Cl− channels, thereby inducing intestinal fluid secretion[9,10]. Kampo medicines are mixtures of numerous herbal plant extracts. It is often undetermined which herbal components exert secretagogue actions as potent laxatives. JCT consists of 10 herb plant extracts including Rhei Rhizoma (rhubarb in English or Daio in Japanese), Cannabis Fructus (hemp fruit or Mashinin), Armeniacae Semen (apricot kernel or Kyonin), Persicae Semen (peach kernel or Tonin), Magnoliae Cortex (magnolia bark or Koboku), Aurantii Fructus Immaturus (immature orange or Kijitsu), Glycyrrhizae radix (glycyrrhiza or Kanzo), Rehmanniae Radix (rehmannia root or Jio), Angelicae Acutilobae Radix (Japanese angelic root or Toki), and Scutellariae Radix (scutellaria root or Ogon). The present study aimed to determine whether these four herbal mixtures exert secretory actions and the mechanisms underlying their secretory actions in colonic epithelial cells

Methods

Results

Conclusion