A natural plant-derived dihydroisosteviol prevents cholera toxin-induced intestinal fluid secretion.
Stevioside and its major metabolite, steviol, have been reported to affect ion transport in many types of tissues, such as the 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 IC(50) values of 101, 100, 9.6, and 50 microM, respectively, whereas the parent compound stevioside had no effect. Apical Cl(-) current measurement indicated that dihydroisosteviol targeted the cystic fibrosis transmembrane regulator (CFTR). The inhibitory action of dihydroisosteviol was reversible and was not associated with changes in the 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 microM dihydroisosteviol reduced intestinal fluid secretion by 88.2% without altering fluid absorption. These results indicate that dihydroisosteviol and similar compounds could be a new class of CFTR inhibitors that may be useful for further development as antidiarrheal agents.
Pariwat
Prapapimon
P
Department of Physiology, Faculty of Science, Mahidol University, Rama 6 Rd., Phayathai, Bangkok 10400, Thailand.
Homvisasevongsa
Sureeporn
S
Muanprasat
Chatchai
C
Chatsudthipong
Varanuj
V
D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002772:Cholera Toxin / Q000633:toxicity*; D045786:Diterpenes, Kaurane / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005960:Glucosides / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007419:Intestinal Secretions / Q000187:drug effects* / Q000378:metabolism; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*
D045786:Diterpenes, Kaurane; D005960:Glucosides; D010936:Plant Extracts; C012043:stevioside; C012042:steviol; D002772:Cholera Toxin