Atpbinding Cassette Abc Transporters

P-glycoprotein, which is encoded by multidrug resistance (mdr) 1a (Abcb1a), mdr1b (Abcb1b), or mdr2 (Abcb4), exhibits a protective role by restricting the entry of a wide variety of xenobiotics (e.g., cyclosporine A, rhodamine 123, mitoxantrone, and doxorubicin). P-glycoprotein is present at the luminal membrane of the inner BRB (2, 60), and the expression of mdrla mRNA is 200- and 24-fold greater than that of mdrlb and mdr2, respectively, in isolated rat retinal vascular endothelial cells (Fig. 2D) (11). Moreover, no cyclosporine A is detected in the intraocular tissues of cyclosporine A-treated rabbits, although the blood level of cyclosporine A was within the therapeutic window (61). TR-iBRB cells express P-glycoprotein (12), and rhodamine 123 accumulation in TR-iBRB cells is enhanced in the presence of inhibitors of P-glycoprotein (62).

ATP-binding cassette transporter G2 (Abcg2) is also known to act as an efflux transporter and is reported to be expressed at the luminal membrane of the inner BRB (63). Abcg2 shows great affinity for not only drugs (e.g., mitoxantrone and doxorubicin), but also photosensitive toxins including pheophorbide-a, a chlorophyll-derived dietary pho-totoxin related to porphyrin. The retina is subject to high levels of cumulative irradiation and, therefore, is vulnerable to light-induced damage caused by a variety of photo-toxic compounds including porphyrins (64). TR-iBRB cells express Abcg2 protein and Ko143, an Abcg2 inhibitor, inhibits the excretion of pheophorbide-a from TR-iBRB cells (63). Taking these findings into consideration, mdrla-encoding P-glycoptorein, as

Fig. 5. Hypothetical localization and physiological function of the inner blood-retinal barrier transporters. Inner blood-retinal barrier transporters play an essential role in supplying nutrients to the retina and carrying out the efflux transport of neurotransmitter metabolites, toxins, and xenobiotics to maintain a constant milieu in the neural retina.

Fig. 5. Hypothetical localization and physiological function of the inner blood-retinal barrier transporters. Inner blood-retinal barrier transporters play an essential role in supplying nutrients to the retina and carrying out the efflux transport of neurotransmitter metabolites, toxins, and xenobiotics to maintain a constant milieu in the neural retina.

well as Abcg2 at the luminal membrane of the inner BRB, could act by restricting the distribution of xenobiotics, including drugs and phototoxins, in the retina. However, the contribution of each ABC transporter subtype to the inner BRB efflux transport is an important issue that remains to be resolved.

0 0

Post a comment