One of the main clinical issues of ABCB together

One of the main clinical issues of ABCB1, together with its impact on intestinal absorption, concerns its location at the BBB. Indeed, ABCB1 has been identified in the luminal side of endothelial cells and in the abluminal side of astrocyte endfeet processes of the CNS microvasculature [[36], [37], [38]]. Moreover, ABCB1 is currently known to be upregulated in neurons and astrocytes of the epileptogenic IC-87114 [[39], [40], [41], [42]]. The aforementioned ABCB1 location will promote an active drug removal from the brain parenchyma, including high BBB permeability compounds that passively diffuse through the membrane. In the choroid plexus ABCB1 seems to contribute to higher concentration of its substrates at the CSF, due to its location in the luminal side of choroidal epithelial cells. This would suggest ABCB1 can increase the concentration of xenobiotics at the CFS, although it is unknown whether this transport significantly contributes to toxicity in CFS-exposed regions [36,43]. Another group of ABC efflux transporters involved in multidrug resistance are ABCCs. The ABCC subfamily is a group of efflux proteins composed of 13 members. Among them, nine are associated to multidrug resistance (ABCC1-ABCC9) [44]. Their chromosomal location is heterogeneous, with each protein associated to a specific location usually in different chromosomes [26]. The most studied transporters are ABCC1-ABCC6, which are importantly expressed in different levels in healthy and epileptogenic brain tissues [[45], [46], [47], [48]], as later referred in Section 4.1. Their tissue distribution is varied and depends on each subtype: while ABCC1 and ABCC5 have an ubiquitous distribution, ABCC2, ABCC3 and ABCC6 are mainly distributed in the liver, small intestine, kidneys and in some secretory organs [44]. In the CNS, ABCC1, ABCC2 and ABCC3 are located in the choroid plexus of the BCSFB, with differential distribution [29,36]. ABCC1, ABCC2, ABCC4 and ABCC5 were also identified in endothelial cells of the BBB, although their expression and cellular localization in these cells is still controversial and remains to be determined36,37]. Several members of the ABCC family are known to be expressed in brain capillary endothelial cells, but only those expressed in the luminal (apical) membrane will actively contribute to the excretory function of the BBB. In this regard only ABCC1, ABCC2, ABCC4 and ABCC5 have been identified in the luminal (apical) membrane of brain capillary endothelial cells[45]. The apical membrane localization of ABCC1 and ABCC2 in brain capillary endothelial cells together with their overexpression in epileptogenic brain tissue (discussed in Section 4.1) is suggestive of their potential role in central-drug resistance. ABCG2 is another transporter from the ABC family thought to be involved in multidrug resistance. This 655 amino acid ABC transporter, is encoded by the ABCG2 gene located on chromosome 4q22 [26]. It has an unusual structure compared to its family members as previously discussed, since ABCG2 is a half-transporter, requiring the formation of homo or heterodimers to actively function [49]. ABCG2 is expressed in a variety of tissues, having its peak of expression in the placental tissue, brain, liver, kidneys, small intestine and colon [50]. ABCG2 also has a wide range of substrates, most of them in parallel with ABCB1, including negative to positively charged molecules, organic anions and sulphate conjugates [49]. A synergistic effect of ABCB1 and ABCG2 has been proposed, due to their overlap of substrate specificity. This was shown when comparing substrate pharmacokinetics in 3 knockout mice models: Abcb1a/1b(-/-), Abcg2(-/-) and Abcb1a/1b(-/-)/Abcg2(-/-) mice [51]. In this study, Kodaira et al [51]. observed a marked increase in the brain-to-plasma ratios of 3 common substrates (erlotinib, flavopiridol and mitoxantrone) in double knockout Abcb1a/1b (-/-)/Abcg2 (-/-) mice compared to the single knockouts Abcb1a/1b (-/-) and Abcg2 (-/-) mice. The synergistic effect of Abcb1 and Abcg2 on the brain-to-plasma ratio was explained by their contribution to the net efflux at the BBB, without any direct interaction between Abcb1 and Abcg2 [51].