The ABC transporter BCRP was first cloned from a doxorubicin-resistant MCF7 breast cancer cell line (MCF-7/AdrVp) by Doyle et al. (1998). Subsequently, other groups cloned the BCRP cDNA sequence from other sources and designated the gene either MXR (mitoxantrone resistance protein) or ABCP (placental ABC protein) (Allikmets et al., 1998; Maliepaard et al., 1999). Since structural and sequence homology revealed that BCRP belongs to the ABCG gene subfamily, the Human Genome Nomenclature Committee conferred the official designation as ABCG2 (Table 7.1). BCRP consists of six putative TMD involved in drug binding and efflux, as well as a single amino-terminal cytosolic NBD that functions as an ABC involved in ATP hydrolysis. BCRP has been suggested to be a half-transporter that may function as a homodimer or tetramer bridged by disulfide bonds (Xu et al., 2004).
Study of BCRP tissue localization shows that it is expressed in the small intestine, colon, liver, placental syncytiotrophoblasts, and ovary (Maliepaard et al., 2001). Further, a monoclonal antibody directed against BCRP used for immuno-histochemical staining revealed prominent expression at the apical membrane of the small intestinal, colonic epithelia, and in hepatocyte canalicular membranes (Scheffer et al., 2000; Maliepaard et al., 2001). Comparatively, BCRP mRNA expression was found to be higher than all other ABC transporters measured (MDR1, MDR3, MRP1-6) in human jejunal mucosa biopsies obtained from 13 healthy volunteers (Taipalensuu et al., 2001). Moreover, with villin-normalized data expression levels between Caco-2 cells versus jejunal samples varied less than 2.5-fold for ABC transporter genes, whereas Caco-2 cells exhibited a 100fold lower transcript copy number in contrast to the human jejunum for BCRP (Taipalensuu et al., 2001). Furthermore, later passage (p56) Caco-2 cells showed higher expression levels of BCRP in comparison to earlier passage (p33) cells, suggesting culturing conditions or epigenetic factors also influence BCRP expression (Taipalensuu et al., 2001). Immunofluorescence studies demonstrated the polarized apical membrane expression of BCRP in Caco-2 cells (Xia et al., 2005).
BCRP mRNA expression quantified by quantitative real-time PCR along the GI tract of 14 healthy subjects demonstrated expression to be maximal in the duodenum and continuously decreasing toward the rectum (terminal ileum 93.7%, ascending colon 75.8%, transverse colon 66.6%, descending colon 62.8%, and sigmoid colon 50.1% compared to duodenum, respectively) (Gutmann et al., 2005).
Interestingly, gender-based variation was also observed for BCRP expression, although the biological relevance of these data has not yet been elucidated.
BCRP transports estrone 3-sulfate and 17|3-estradiol-3-sulfate, while the parent steroids are not substrates (Imai et al., 2003). BCRP also transports the active glucuronide conjugate metabolite of SN-38 (SN-38-glucuronide) with an approximately sevenfold lower affinity than the parent SN-38 itself, suggesting the involvement of BCRP in transporting glucuronide conjugated compounds (Nakatomi et al., 2001). BCRP also mediates the secretion of other clinically important camptothecans, such as topotecan. Jonker et al. (2000) observed a more than sixfold decrease in topotecan plasma concentrations upon concomitant administration of GF120918 (an inhibitor of both P-gp and BCRP), in P-gp deficient mice. This study shows that BCRP mediates apically directed drug transport, which would reduce drug bioavailability. As such, the coadministration of an effective BCRP inhibitor may increase the oral bioavailability of topotecan. Interestingly, fumitremorgin C, an extract of Aspergillus fumigatus, selectively inhibits BCRP with no overlapping affinity for P-gp, as demonstrated by reversing resistance mediated by MCF-7 cells transfected with the BCRP gene (Rabindran et al., 1998; Ozvegy et al., 2001). These observations suggest that the oral absorption of therapeutic compounds specifically designed to be substrates of BCRP would be enhanced. A more comprehensive summary of various BCRP substrates can be found in Table 7.4.
Table 7.4. Partial list of compounds shown to interact with breast cancer resistance proteins
Camptothecins (SN-38, topotecan)
Endogenous substrates Estrone 3-sulfate 17 ß-estradiol sulfate 17ß-Estradiol 17-(ß-D-glucuronide Folic acid Protoporphyrin IX
Fluorescent dyes BODIPY-Prazosin Hoechst 33342 BBR3390
Fumitremorgin C Tamoxifen
HIV protease Inhibitors
The table has been modified from the information published by Sarkadi et al. (2004), Leslie et al. (2005) and Staud and Pavek (2005)
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