such as PAH, 6-MP, and b-lactam antibiotics (Uchida et al. 2007). MRP4 mRNA is expressed abundantly in isolated mouse and rat RVEC (Hosoya and Tachikawa 2009; Tachikawa et al. 2008). It has been demonstrated that MRP4 is localized on the luminal membrane of mouse RVEC (Tagami et al. 2009). These findings suggest that MRP4 is involved in the retina-to-blood efflux transport of b-lactam antibiotics and 6-MP across the inner BRB. MRP4 is not the only multidrug resistance-associated protein expressed in inner BRB cells. MRP3 (ABCC3) and MRP6 (ABCC6) mRNAs are also expressed in isolated mouse RVEC (Tachikawa et al. 2008). RPE cells also have MRP functional activity as evident from studies with primary cultures of human RPE cells (Aukunuru et al. 2001). The aldose reductase inhibitor BAPSG, which has potential for treatment of diabetic retinopathy, is a substrate for this efflux process (Aukunuru et al. 2001). Among the six genes coding for MRPs, MRP1, MRP4, and MRP5 are expressed in human RPE cell lines (Mannermaa et al. 2009). Permeability of fluorescein (a substrate for MRPs) across the porcine RPE tissue sheets was greater in the retina-to-choroid direction compared with that in the opposite direction. MRP inhibitors increase the accumulation of fluorescein in the RPE cells. These findings suggest that MRPs are located on the basolateral membrane of the RPE cells (Aukunuru et al. 2001; Steuer et al. 2005).

4.3.5  Breast Cancer Resistance Protein (BCRP/ABCG2/

MXR/ABCP)

Recent studies using ABCG2 knockout mice reveal that ABCG2 can actively extrude a variety of xenobiotics and drugs across biological membranes (Vlaming et al. 2009). ABCG2 recognizes as its substrates not only drugs such as mitoxantrone and doxorubicin, but also photosensitive toxins such as pheophorbide a, a chlorophyll-derived dietary phototoxin related to porphyrin. ABCG2 is expressed on the luminal membrane of RVEC (Asashima et al. 2006). In vitro studies have demonstrated that ABCG2 mediates the excretion of pheophorbide a from TR-iBRB cells (Asashima et al. 2006). Because the retina is subject to high levels of cumulative irradiation, ABCG2 may protect the retina from the phototoxicity caused by the circulating phototoxins including pheophorbide a. ABCG2 is expressed in D407 cells but not in any other RPE cell line (Mannermaa et al. 2009). Whether RPE cells expresses this efflux transporter in vivo has not been investigated.

4.3.6  ABCAs

ABCA transporters play an essential role in the efflux of endogenous lipids such as sterols, phospholipids, and retinoids from cells. ABCA3 and ABCA9 mRNAs are highly expressed in isolated mouse RVEC (Tachikawa et al. 2008).