Expression of Efflux Transporters in Human Ocular Tissues

Abstract

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.

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

“…2). Thus, it is not clear based on this discrepancy The studies by Chen et al (2013), Dahlin et al (2013), Lee et al (2015), Pelis et al (2009) (Fig. 2).…”

“…The majority of the studies observed mRNA for MRP1, MRP2, MRP3, MRP4, MRP5, MRP6, MRP7, BCRP, and P-gp in either ciliary body or iris-ciliary body preparations, with only a few discrepancies. 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 .…”

“…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.…”

“…1). Although Pelis et al (2009) detected BCRP in the human ciliary body from a single donor by immunoblotting, another study failed to detect BCRP protein expression in iris-ciliary body from multiple donors (Chen et al, 2013). MRP2 localizes to the apical membrane of nonpigmented epithelial cells of the human pars plana and plicata (Pelis et al, 2009), whereas MRP4 is located in the basolateral membrane of pigmented cells (Lee et al, 2015) (Fig.…”

“…P-gp) showed the highest expression level in the human ciliary body. At the protein level (immunoblotting), MRP1, MRP2, MRP3, MRP4, MRP6, MRP7, and P-gp were detected in the human iris-ciliary body (Chen et al, 2013), and MRP1, MRP2, MRP4, BCRP, and P-gp were detected in the human ciliary body (Pelis et al, 2009) (Fig. 1).…”