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

The Journal of Biological Chemistry
Changsuk MoonAnjaparavanda P Naren

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.

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Citations

Oct 3, 2015·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Changsuk MoonAnjaparavanda P Naren
Aug 27, 2016·Pharmaceutical Biology·Xianxiang XuTingliang Jiang
Jan 11, 2018·International Journal of Molecular Sciences·Risako KonKiyoshi Sugiyama
Feb 23, 2018·JCI Insight·John J BrewingtonJohn P Clancy
Aug 16, 2018·The Journal of Pharmacology and Experimental Therapeutics·Gabriela Maria BertollottoFabiola Zakia Mónica
Jun 21, 2015·Pharmacological Reviews·Dustin R WalshPeter A Friedman
Jul 8, 2015·The Journal of Pharmacology and Experimental Therapeutics·Jiagen WenWei Zhang
Jun 5, 2016·American Journal of Physiology. Lung Cellular and Molecular Physiology·Kavisha AroraAnjaparavanda P Naren
Jul 10, 2019·Scientific Reports·Yunjie HuangAnjaparavanda P Naren
Jul 18, 2019·Nature Communications·Kyu Shik MunAnjaparavanda P Naren
Oct 6, 2017·JCI Insight·Kavisha AroraAnjaparavanda P Naren
Dec 3, 2020·Cancers·Jakub KryczkaJoanna Boncela
May 6, 2021·American Journal of Physiology. Gastrointestinal and Liver Physiology·Kavisha AroraAnjaparavanda P Naren
Dec 28, 2017·Analytical Chemistry·Dulan B GunasekaraNancy L Allbritton

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