title: Compartmentalized accumulation of cAMP near complexes of multidrug resistance protein 4 (MRP4) and cystic fibrosis transmembrane conductance regulator (CFTR) contributes to drug-induced diarrhea.
abstract: Diarrhea is one of the most common adverse side effects observed in ∼7% of individuals consuming Food and Drug Administration (FDA)-approved drugs. The mechanism of how these drugs alter fluid secretion in the gut and induce diarrhea is not clearly understood. Several drugs are either substrates or inhibitors of multidrug resistance protein 4 (MRP4), such as the anti-colon cancer drug irinotecan and an anti-retroviral used to treat HIV infection, 3'-azido-3'-deoxythymidine (AZT). These drugs activate cystic fibrosis transmembrane conductance regulator (CFTR)-mediated fluid secretion by inhibiting MRP4-mediated cAMP efflux. Binding of drugs to MRP4 augments the formation of MRP4-CFTR-containing macromolecular complexes that is mediated via scaffolding protein PDZK1. Importantly, HIV patients on AZT treatment demonstrate augmented MRP4-CFTR complex formation in the colon, which defines a novel paradigm of drug-induced diarrhea.
authors.affiliation: From the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, the Departments of Physiology and.
authors.forename: Changsuk
authors.initials: C
authors.lastname: Moon
authors.affiliation: the Departments of Physiology and Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: the Departments of Physiology and the Departments of Hematology and.
authors.forename: Aixia
authors.initials: A
authors.lastname: Ren
authors.affiliation: From the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, the Departments of Physiology and.
authors.forename: Kavisha
authors.initials: K
authors.lastname: Arora
authors.affiliation: the Departments of Physiology and.
authors.forename: Chandrima
authors.initials: C
authors.lastname: Sinha
authors.affiliation: From the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, the Departments of Physiology and.
authors.forename: Sunitha
authors.initials: S
authors.lastname: Yarlagadda
authors.affiliation: From the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.
authors.forename: Koryse
authors.initials: K
authors.lastname: Woodrooffe
authors.affiliation: Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors.forename: John D
authors.initials: JD
authors.lastname: Schuetz
authors.affiliation: the Department of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, Kansas 66047.
authors.forename: Koteswara Rao
authors.initials: KR
authors.lastname: Valasani
authors.affiliation: the Department of Gastroenterology and Hepatology, Erasmus University Medical Center, 3000CA Rotterdam, The Netherlands.
authors.forename: Hugo R
authors.initials: HR
authors.lastname: de Jonge
authors.affiliation: From the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.
authors.forename: Shiva Kumar
authors.initials: SK
authors.lastname: Shanmukhappa
authors.affiliation: the Division of Digestive Diseases, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, and.
authors.forename: Mohamed Tarek M
authors.initials: MT
authors.lastname: Shata
authors.affiliation: the Department of Health and Sport Sciences, University of Memphis, Memphis, Tennessee 38152.
authors.forename: Randal K
authors.initials: RK
authors.lastname: Buddington
authors.affiliation: the Departments of Physiology and.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Parthasarathi
authors.affiliation: From the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, the Departments of Physiology and anaren@cchmc.org.
authors.forename: Anjaparavanda P
authors.initials: AP
authors.lastname: Naren
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives; D000242:Cyclic AMP / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D003967:Diarrhea / Q000139:chemically induced*; D017277:Drug Approval; D019073:HT29 Cells; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D000077146:Irinotecan; D051379:Mice; D008958:Models, Molecular; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D011487:Protein Conformation; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D002166:Camptothecin; D000242:Cyclic AMP; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000077146:Irinotecan; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C489540:Abcc4 protein, mouse
keywords: ABC Transporter; Chloride Channel; Chloride Transport; Cyclic AMP (cAMP); Cystic Fibrosis Transmembrane Conductance Regulator (CFTR); Drug-induced Secretory Diarrhea; Enterosphere; MRP4; Multidrug Transporter; PDZ Domain