Efflux Protein Expression in Human Retinal Pigment Epithelium Cell Lines

Mannermaa, Eliisa; Vellonen, Kati‐Sisko; Ryhänen, Tuomas; Kokkonen, Katriina; Ranta, Veli‐Pekka; Kaarniranta, Kai; Urtti, Arto

doi:10.1007/s11095-009-9890-6

Cited by 72 publications

(71 citation statements)

References 50 publications

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“…Although lipophilicity could be correlated with drug partitioning and delivery in this study, we cannot rule out the dependence of ␤-blocker delivery or tissue uptake on other factors. For example, ␤-blockers might be transported via transporters such as P-glycoprotein, organic cation transporters, and ATP-binding cassette G2/breast cancer resistance protein transporter that are known to be present in the retinal pigment epithelium (Mannermaa et al, 2009). In this study also, we cannot rule out such possibilities for drug interactions.…”

Section: ␤-Blockermentioning

confidence: 88%

RETRACTION: Influence of Lipophilicity on Drug Partitioning into Sclera, Choroid-Retinal Pigment Epithelium, Retina, Trabecular Meshwork, and Optic Nerve

Kadam

Kompella

2009

J Pharmacol Exp Ther

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In vitro bovine eye tissue/phosphate-buffered saline, pH 7.4, partition coefficients (Kt:b), in vitro binding to natural melanin, and in vivo delivery at 1 h after posterior subconjunctival injection in Brown Norway rats were determined for eight ␤-blockers. The Kt:b was in the order intact tissue, dry weight method Ն intact tissue, wet weight method corrected for tissue water and drug in tissue water Ͼ Ͼ intact tissue, wet weight method Ͼ homogenized tissue. In intact tissue methods, Kt:b followed the order choroid-retinal pigment epithelium (RPE) Ͼ trabecular meshwork Ͼ retina Ͼ sclera ϳ optic nerve; propranolol Ͼ betaxolol Ͼ pindolol ϳ timolol ϳ metoprolol Ͼ sotalol ϳ atenolol ϳ nadolol. Intact tissue, wet weight log (Kt:b) correlated positively with log D for all tissues (R 2 of 0.7-0.9). Log (melanin binding capacity) correlated positively with choroid-RPE log (Kt:b) (R 2 of 0.5). With an increase in concentration, Kt:b decreased in trabecular meshwork for all ␤-blockers and for some lipophilic ␤-blockers in choroid-RPE and sclera. With an increase in drug lipophilicity, in vivo tissue distribution increased in choroid-RPE, iris-ciliary body, sclera, and cornea but exhibited a declining trend in retina, vitreous, and lens. In vitro bovine intact tissue, wet weight Kt:b correlated positively with rat in vivo tissue/vitreous humor distribution for sclera, choroid-RPE, and retina (R 2 of 0.985-0.993). In vitro tissue partition coefficients might be useful in predicting in vivo drug distribution after trans-scleral delivery. Less lipophilic solutes exhibiting limited nonproductive binding in choroid-RPE might exhibit greater transscleral delivery to the retina and vitreous.

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Section: ␤-Blockermentioning

confidence: 88%

RETRACTION: Influence of Lipophilicity on Drug Partitioning into Sclera, Choroid-Retinal Pigment Epithelium, Retina, Trabecular Meshwork, and Optic Nerve

Kadam

Kompella

2009

J Pharmacol Exp Ther

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“…Studies with cultured RPE cell lines have shown that BCRP is expressed only at very low levels. 28 Therefore, we asked first whether this heme exporter is expressed in mouse retina and RPE cells and, if it is, whether it is located differentially in the apical versus basolateral membrane in the RPE. By RT-PCR, we found evidence of the presence of BCRP mRNA in neural retina as well as in RPE eyecup (Fig.…”

Section: Expression Of Bcrp In Mouse Retina and Its Polarized Localizmentioning

confidence: 99%

Polarized Distribution of Heme Transporters in Retinal Pigment Epithelium and Their Regulation in the Iron-Overload Disease Hemochromatosis

Gnana-Prakasam

Reddy²,

Veeranan-Karmegam³

et al. 2011

Invest. Ophthalmol. Vis. Sci.

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“…Therefore, ARPE-19 should be used with caution when in vitro models are used in the efflux transporter research (Constable et al, 2004;Mannermaa et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Expression of Efflux Transporters in Human Ocular Tissues

Chen

Zang

et al. 2013

Drug Metab Dispos

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To investigate the expression profiles of efflux transporters in human ocular tissues, quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry were used to obtain the relative mRNA and protein expressions of various efflux transporters in human ocular tissues. The cornea, conjunctiva, irisciliary body (ICB), retina and choroid, human corneal epithelial cell line (HCEC), and human retinal pigment epithelial cell line (ARPE-19) were examined for the expressions of multidrug resistanceassociated proteins 1-7 (MRP1-7), multidrug resistance 1 (MDR1) P-glycoprotein, lung resistance protein (LRP), and breast cancerresistance protein (BCRP). The expression sites and patterns of efflux transporters were significantly different in ocular tissues, HCEC, and ARPE-19, as well as the expression profiles of efflux transporters in mRNA and protein levels in ocular tissues. At the protein level, MRP1-7, MDR1, and LRP were expressed in the corneal epithelium; MRP1-7, MDR1, LRP, and BCRP were expressed in the conjunctival epithelium; MRP1-2, MRP6-7, MDR1, and LRP were expressed in the ICB; MRP1-3, MRP6-7, MDR1, and LRP were expressed in the retina; MRP1-3, MRP6-7, MDR1, and LRP were expressed in the HCEC; and MRP7, MDR1, LRP, and BCRP were expressed in the ARPE-19. This quantitative and systematic study of efflux transporters in normal ocular tissues and cell lines provides evidence of cross-ocular tissue transporter expression differences, implying that efflux transporter expression variability should be taken into consideration for better understanding of ocular pharmacokinetic and pharmacodynamic data.

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Efflux Protein Expression in Human Retinal Pigment Epithelium Cell Lines

Abstract: MRP1, MRP4 and MRP5 are the main efflux transporters in RPE cell lines. There are differences in efflux protein expression between RPE cell lines.

Cited by 72 publications

References 50 publications

RETRACTION: Influence of Lipophilicity on Drug Partitioning into Sclera, Choroid-Retinal Pigment Epithelium, Retina, Trabecular Meshwork, and Optic Nerve

RETRACTION: Influence of Lipophilicity on Drug Partitioning into Sclera, Choroid-Retinal Pigment Epithelium, Retina, Trabecular Meshwork, and Optic Nerve

Polarized Distribution of Heme Transporters in Retinal Pigment Epithelium and Their Regulation in the Iron-Overload Disease Hemochromatosis

Expression of Efflux Transporters in Human Ocular Tissues

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