A natural plant derived‐dihydroisosteviol prevents cholera toxin‐induced intestinal fluid secretion

Abstract

Stevioside and its major metabolite, steviol, have been reported to affect ion transport in many types of tissues, such as kidney, pancreas and intestine. The effect of stevioside, steviol and its analogs on intestinal Cl− secretion was investigated in a human T84 epithelial cell line. Short circuit current measurements showed that steviol, and analogs, isosteviol, dihydroisosteviol and isosteviol 16‐oxime, inhibited in a dose‐dependent manner forskolin‐induced Cl− secretion with IC50 of 101, 100, 9.6 and 50 μM, respectively, whereas the parent compound stevioside had no effect. Apical Cl− current measurement indicated that dihydroisosteviol targeted CFTR. The inhibitory action of dihydroisosteviol was reversible and was not associated with changes in intracellular cAMP level. In addition, dihydroisosteviol did not affect calcium‐activated chloride secretion and T84 cell viability. In vivo studies using a mouse closed loop model of cholera toxin‐induced intestinal fluid secretion showed that intraluminal injection of 50 μM dihydroisosteviol reduced intestinal fluid secretion by 89% without altering fluid absorption. These results indicate that dihydroisosteviol and similar compounds could be a new class of CFTR inhibitors useful for further development as antidiarrheal agents.