Changes in the Expression of Aquaporin-3 in the Gastrointestinal Tract Affect Drug Absorption.

Nobutomo Ikarashi,Risako Kon,Chika Nagoya,Kiyoshi Sugiyama,Satoshi Kitaoka,Masayo Saito,Wataru Ochiai,Sayuri Kajiwara,Akane Kawabata

doi:10.3390/ijms20071559

Nobutomo Ikarashi, Risako Kon + Show 7 more

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https://doi.org/10.3390/ijms20071559

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Abstract

Aquaporin-3 (AQP3) plays an important role in water transport in the gastrointestinal (GI) tract. In this study, we conducted a Caco-2 cell permeability assay to examine how changes in the expression and function of AQP3 affect the rate at which a drug is absorbed via passive transport in the GI tract. When the function of AQP3 was inhibited by mercuric chloride or phloretin, there was no change in warfarin permeability. In contrast, when the expression of AQP3 protein was decreased by prostaglandin E2 (PGE2) treatment, warfarin permeability increased to approximately twice the control level, and membrane fluidity increased by 15%. In addition, warfarin permeability increased to an extent comparable to that after PGE2 treatment when cell membrane fluidity was increased by 10% via boric acid/EDTA treatment. These findings suggest the possibility that the increased drug absorption under decreased AQP3 expression was attributable to increased membrane fluidity. The results of this study demonstrate that the rate of water transport has little effect on drug absorption. However, our findings also indicate that although AQP3 and other similar transmembrane proteins do not themselves transport drugs, changes in their expression levels can cause changes in cell membrane fluidity, thus affecting drug absorption rates.

Highlights

Aquaporins (AQPs) play an important role in water transport in the body [1]
transepithelial electrical resistance (TEER) again increased from day 15 onwards, reaching approximately 1800 Ω·cm2 on day 21. These results are consistent with previous reports [26] and confirm that in this experiment, Caco-2 cells differentiated into small intestinal epithelial-like cells by day 21 of incubation and formed a membrane consisting of a monolayer of cells with tight junctions (Figure 1A)
When incubated in a Transwell plate for 21 days, Caco-2 cells differentiate into small intestinal epithWelihael-nlikineccuebllast.eAdsinobasTerrvaendswineltlhpelsamteaflol rin2t1esdtianyes,dCifafceore-2ntciaetllesddCifafceore-2ntciealtles ienxtporessmsatlrlainnstpeostritnearsl esupicthhealsiaPl--lgikpeancdelolsr.gaAnsic aonbisoenrvterdansipnortthinegspmoalyllpeipnttiedsetin(Oe,ATdPif)f;etrhenutsi,atthedeseCcaecllos-2arecewllisdeelyxpurseesds tfroarnasspsoerstsemrsesnutschofasdrPu-ggpaabnsodrportigoanniicnatnhieonsmtraalnl sinptoersttiinngep[2o5ly].peCpatcidoe-2(OceAllTs Pe)x;ptrheusss, AthQesPescaenllds aarree wfreidqeuleyntulsyeudsefodrinasrseelsesvmanetnststuodfiedsr, uegspaebcisaolrlypttihoonseinonthAe QsmP3al[l35in–3te7s]t.inIne t[h2i5s]s.tCudacyo, w-2ecuesllesdeCxpacroes-2s AceQllsPstoainndveasrteigfarteequtheenrtloyleuosfedAQinPr3eilnevtahnetGsItuadbiseosr,petsiponecoiafldlyruthgso.se on AQP3 [35,36,37]

Summary

Introduction

AQPs are membrane proteins with six transmembrane domains and a molecular weight of approximately 30 kDa [2]. These proteins have two asparagine–proline–alanine (Asn-Pro-Ala; NPA) boxes and allow water and glycerol molecules to selectively pass through the membrane along an osmotic gradient [3,4,5]. It has become clear that diarrhea and constipation can be caused by changes in the expression or function of AQP3, indicating that AQP3 is a very important functional protein for water transport in the GI tract [13,14,15,16,17,18]

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