title: Inhibition of intestinal chloride secretion by piperine as a cellular basis for the anti-secretory effect of black peppers.
abstract: Piperine is the principal alkaloid in black peppers (Piper nigrum L.), which is a commonly included spice in anti-diarrheal formulations. Piperine has antispasmodic activities, but its anti-secretory effect is not known. Therefore, this study investigated the anti-secretory effect of piperine and its underlying mechanism. Piperine inhibited cAMP-mediated Cl- secretion in human intestinal epithelial (T84) cells, similar to black pepper extract. Intraluminal administration of piperine (2 μg/loop) suppressed cholera toxin-induced intestinal fluid accumulation by ∼85% in mice. The anti-secretory mechanism of piperine was investigated by evaluating its effects on the activity of transport proteins involved in cAMP-mediated Cl- secretion. Notably, piperine inhibited CFTR Cl- channel activity (IC50#8'6#10 μM) without affecting intracellular cAMP levels. The mechanisms of piperine-induced CFTR inhibition did not involve MRP4-mediated cAMP efflux, AMPK or TRPV1. Piperine also inhibited cAMP-activated basolateral K+ channels, but it had no effect on Na+-K+-Cl- cotransporters or Na+-K+ ATPases. Piperine suppressed Ca2+-activated Cl- channels (CaCC) without affecting intracellular Ca2+ concentrations or Ca2+-activated basolateral K+ channels. Collectively, this study indicates that the anti-secretory effect of piperine involves the inhibition of CFTR, CaCC and cAMP-activated basolateral K+ channels. Piperine represents a novel class of drug candidates for the treatment of diarrheal diseases caused by the intestinal hypersecretion of Cl-.
authors: Department of Physiology, Faculty of Science, Mahidol University, Rama 6 Road, Ratchathewee, Bangkok, Thailand.
authors: Pawin
authors: P
authors: Pongkorpsakol
authors: Department of Physiology, Faculty of Science, Mahidol University, Rama 6 Road, Ratchathewee, Bangkok, Thailand.
authors: Preedajit
authors: P
authors: Wongkrasant
authors: Department of Chemistry, Faculty of Science and Technology, Suan Sunandha Rajabhat University, Dusit, Bangkok, Thailand.
authors: Saowanee
authors: S
authors: Kumpun
authors: Department of Physiology, Faculty of Science, Mahidol University, Rama 6 Road, Ratchathewee, Bangkok, Thailand; Excellent Center for Drug Discovery, Thailand Center of Excellence for Life Sciences (TCELS), Bangkok, Thailand.
authors: Varanuj
authors: V
authors: Chatsudthipong
authors: Department of Physiology, Faculty of Science, Mahidol University, Rama 6 Road, Ratchathewee, Bangkok, Thailand; Excellent Center for Drug Discovery, Thailand Center of Excellence for Life Sciences (TCELS), Bangkok, Thailand; Center of Excellence on Environmental Health and Toxicology, Ministry of Education, Bangkok, Thailand. Electronic address: chatchai.mua@mahidol.ac.th.
authors: Chatchai
authors: C
authors: Muanprasat
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002712:Chlorides / Q000378:metabolism*; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008297:Male; D051379:Mice; D018181:Mice, Inbred CFTR; D029222:Piper nigrum / Q000737:chemistry*; D010880:Piperidines / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: D000470:Alkaloids; D052117:Benzodioxoles; D002712:Chlorides; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002772:Cholera Toxin; D000242:Cyclic AMP; D000254:Sodium-Potassium-Exchanging ATPase; C008922:piperine
keywords: Black pepper; CFTR; Cholera; Diarrhea; Piperine