title: Drug-induced secretory diarrhea: A role for CFTR.
abstract: Many medications induce diarrhea as a side effect, which can be a major obstacle to therapeutic efficacy and also a life-threatening condition. Secretory diarrhea can be caused by excessive fluid secretion in the intestine under pathological conditions. The cAMP/cGMP-regulated cystic fibrosis transmembrane conductance regulator (CFTR) is the primary chloride channel at the apical membrane of intestinal epithelial cells and plays a major role in intestinal fluid secretion and homeostasis. CFTR forms macromolecular complexes at discreet microdomains at the plasma membrane, and its chloride channel function is regulated spatiotemporally through protein-protein interactions and cAMP/cGMP-mediated signaling. Drugs that perturb CFTR-containing macromolecular complexes in the intestinal epithelium and upregulate intracellular cAMP and/or cGMP levels can hyperactivate the CFTR channel, causing excessive fluid secretion and secretory diarrhea. Inhibition of CFTR chloride-channel activity may represent a novel approach to the management of drug-induced secretory diarrhea.
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Changsuk
authors.initials: C
authors.lastname: Moon
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.|Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Nambirajan
authors.initials: N
authors.lastname: Sundaram
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Sunitha
authors.initials: S
authors.lastname: Yarlagadda
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Vadde Sudhakar
authors.initials: VS
authors.lastname: Reddy
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Kavisha
authors.initials: K
authors.lastname: Arora
authors.affiliation: Department of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.|Department of General Surgery, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Helmrath
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Anjaparavanda P
authors.initials: AP
authors.lastname: Naren
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D003967:Diarrhea / Q000139:chemically induced* / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions / Q000378:metabolism*; D006801:Humans
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP; D006152:Cyclic GMP
keywords: CFTR chloride channel; CFTR inhibitor; CFTR-containing macromolecular complex; Drug-induced diarrhea; Intestinal fluid secretion