Compartmentalized Accumulation of cAMP near Complexes of Multidrug Resistance Protein 4 (MRP4) and Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Contributes to Drug-induced Diarrhea

• Published in: The Journal of biological chemistry Vol. 290; no. 18; pp. 11246 - 11257
• Main Authors: Moon, Changsuk, Zhang, Weiqiang, Ren, Aixia, Arora, Kavisha, Sinha, Chandrima, Yarlagadda, Sunitha, Woodrooffe, Koryse, Schuetz, John D., Valasani, Koteswara Rao, de Jonge, Hugo R., Shanmukhappa, Shiva Kumar, Shata, Mohamed Tarek M., Buddington, Randal K., Parthasarathi, Kaushik, Naren, Anjaparavanda P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2015; American Society for Biochemistry and Molecular Biology
• Subjects: ABC Transporter; Animals; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Cell Biology; Chloride Channel; Chloride Transport; Cyclic AMP (cAMP); Cyclic AMP - metabolism; Cystic Fibrosis Transmembrane Conductance Regulator (CFTR); Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Diarrhea - chemically induced; Drug Approval; Drug-induced Secretory Diarrhea; Enterosphere; HT29 Cells; Humans; Intracellular Space - drug effects; Intracellular Space - metabolism; Irinotecan; Mice; Models, Molecular; MRP4; Multidrug Resistance-Associated Proteins - chemistry; Multidrug Resistance-Associated Proteins - deficiency; Multidrug Resistance-Associated Proteins - metabolism; Multidrug Transporter; PDZ Domain; Protein Conformation; United States; United States Food and Drug Administration; Chloride Channel; PDZ Domain; Drug-induced Secretory Diarrhea; ABC Transporter; Chloride Transport; Cystic Fibrosis Transmembrane Conductance Regulator (CFTR); Multidrug Transporter; Enterosphere; MRP4; Cyclic AMP (cAMP)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.605410

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. Background: Diarrhea is an adverse side effect associated with many therapeutics. Results: Irinotecan induced hyperactive cystic fibrosis transmembrane conductance regulator (CFTR) function by inhibiting multidrug resistance protein 4 (MRP4) and formation of MRP4-CFTR macromolecular complexes. Conclusion: MRP4-CFTR-containing macromolecular complexes play an important role in drug-induced diarrhea. Significance: These studies help define molecular mechanisms of drug-induced diarrhea.