Gene Expression Profiling of Transporters in the Solute Carrier and ATP-Binding Cassette Superfamilies in Human Eye Substructures

Abstract

The barrier epithelia of the cornea and retina control drug and nutrient access to various compartments of the human eye. While ocular transporters are likely to play a critical role in homeostasis and drug delivery, little is known about their expression, localization and function. In this study, the mRNA expression levels of 445 transporters, metabolic enzymes, transcription factors and nuclear receptors were profiled in five regions of the human eye: cornea, iris, ciliary body, choroid and retina. Through RNA expression profiling and immunohistochemistry, several transporters were identified as putative targets for drug transport in ocular tissues. Our analysis identified SLC22A7 (OAT2), a carrier for the anti-viral drug, acyclovir, in the corneal epithelium, in addition to ABCG2 (BCRP), an important xenobiotic efflux pump, in retinal nerve fibers and the retinal pigment epithelium. Collectively, our results provide an understanding of the transporters that serve to maintain ocular homeostasis and which may be potential targets for drug delivery to deep compartments of the eye.

Drug Transport by the Blood-Aqueous Humor Barrier of the Eye

“…Several studies have examined mRNA (using reverse-transcription polymerase chain reaction, quantitative polymerase chain reaction, or microarray) expression of ABC drug transporters in isolated human irisciliary body (Zhang et al, 2008;Chen et al, 2013) or in preparations containing only human iris or ciliary body that were isolated separately by microdissection (Pelis et al, 2009;Dahlin et al, 2013;Lee et al, 2015). Table 1 summarizes the findings from these studies.…”

“…For example, Chen et al (2013) failed to observe mRNA for MRP3 in iris-ciliary body, whereas Zhang et al (2008) did not detect MRP2 mRNA in iris-ciliary body. Of the ABC transporter genes examined by Dahlin et al (2013), MRP5 and P-gp (MRP5 . P-gp) showed the highest expression level in the human ciliary body.…”

“…Both transporters are speculated to play a role in effluxing drugs from ciliary epithelial cells into the choroid. In two independent studies, mRNA for MRP1, MRP3, MRP4, MRP5, MRP6, MRP7, and P-gp was detected in the human iris, whereas BCRP was low to undetectable (Dahlin et al, 2013;Lee et al, 2015) (Table 1). Of the ABC transporter genes examined in the iris by Dahlin et al (2013), P-gp and MRP5 (P-gp.MRP5) were the most highly expressed.…”

“…In two independent studies, mRNA for MRP1, MRP3, MRP4, MRP5, MRP6, MRP7, and P-gp was detected in the human iris, whereas BCRP was low to undetectable (Dahlin et al, 2013;Lee et al, 2015) (Table 1). Of the ABC transporter genes examined in the iris by Dahlin et al (2013), P-gp and MRP5 (P-gp.MRP5) were the most highly expressed. Although Dahlin et al (2013) detected MRP2 mRNA in the human iris, Lee et al (2015) did not.…”

Drug Transporters in the Central Nervous System

“…luminal and abluminal [198], retinal pigmented epithelial cells, basolateral [198] rOATP2B1 retina [195] rOATP3A1 retina [195] rOATP4A1 retina [195,201] retina [201] human OCT1 retinal pigmented epithelium [202] OCT2 retina [194] 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 44 OCT3 retina [194] OCTN2 retina [194] rat rOCT1 retina [195]{ rOCT2 retina [195]{ mouse mOCT3 retinal pigmented epithelial cells [203] mOCTN1 blood retinal capillary epithelial cells [204] mOCTN2 blood retinal capillary epithelial cells [204] rat rOAT2 retina [195] rOAT3 retina [195], Blood retinal capillaries [205] primary cultured blood retinal capillary endothelial cells [205] blood retinal capillary endothelial cells: abluminal …”