Compartmentalized accumulation of cAMP near complexes of multidrug resistance protein 4 (MRP4) and cystic fibrosis transmembrane conductance regulator (CFTR) contributes to drug-induced diarrhea

Changsuk Moon, Weiqiang Zhang, Aixia Ren, Kavisha Arora, Chandrima Sinha, Sunitha Yarlagadda, Koryse Woodrooffe, John D. Schuetz, Koteswara Rao Valasani, Hugo R. De Jonge, Shiva Kumar Shanmukhappa, Mohamed Tarek M. Shata, Randal Buddington, Kaushik Parthasarathi, Anjaparavanda P. Naren

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)11246-11257
Number of pages12
JournalJournal of Biological Chemistry
Volume290
Issue number18
DOIs
StatePublished - May 1 2015

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P-Glycoproteins
Cystic Fibrosis Transmembrane Conductance Regulator
Diarrhea
Pharmaceutical Preparations
Fluids and Secretions
irinotecan
Macromolecular Substances
Fluids
Zidovudine
United States Food and Drug Administration
Colonic Neoplasms
HIV Infections
Colon
HIV
Substrates

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Compartmentalized accumulation of cAMP near complexes of multidrug resistance protein 4 (MRP4) and cystic fibrosis transmembrane conductance regulator (CFTR) contributes to drug-induced diarrhea. / 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; Parthasarathi, Kaushik; Naren, Anjaparavanda P.

In: Journal of Biological Chemistry, Vol. 290, No. 18, 01.05.2015, p. 11246-11257.

Research output: Contribution to journalArticle

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 ; Parthasarathi, Kaushik ; Naren, Anjaparavanda P. / Compartmentalized accumulation of cAMP near complexes of multidrug resistance protein 4 (MRP4) and cystic fibrosis transmembrane conductance regulator (CFTR) contributes to drug-induced diarrhea. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 18. pp. 11246-11257.
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