Drug resistance efflux proteins

Both influx and efflux transporters are located in intestinal epithelial cells and can either increase or decrease oral absorption. Influx transporters such as human peptide transporter 1 (hPEPTl), apical sodium bile acid transporter (ASBT), and nucleoside transporters actively transport drugs that mimic their native substrates across the epithelial cell, whereas efflux transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP) actively pump absorbed drugs back into the intestinal lumen. 

Breast Cancer Resistance Protein (BCRP, also known as MXR or ABCP), first cloned from mitoxantrone and anthracycline-resistant breast and colon cancer cells [188, 189] is a half-transporter efflux pump believed to function as a homo-or hetero-dimer. Following its identification, BCRP-mediated drug resistance was observed for topoisomerase inhibitors including camptothecins [190, 191] and in-dolocarbazoles [192]. In normal tissues, BCRP was detected in placental syncytio-trophoblasts, hepatocyte canalicular membrane, apical intestinal epithelia and vascular endothelial cells [193]. These findings support the important role BCRP plays in modulating topotecan bioavailability, fetal exposure and hepatic elimination [194]. Considering that the substrates and tissue distributions for BCRP overlap somewhat with MDR1 and MRPs [195], additional studies will be required to define the relative contribution of each of these transporters in the overall and tis-... 

Zaman, G.J., Flens, M.J., van Leusden, M.R., de Haas, M., Mulder, H.S., Lankelma, J., Pinedo, H.M., Scheper, R. J., Baas, F. and Broxterman, H.J., (1994) The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. Proceedings of the National Academy of Sciences of the United States of America, 91, 8822-8826. 

Drug resistance in vitro and probably in vivo results both from inhibition of influx of the vinca alkaloids and, perhaps more frequently, from promotion of their efflux out of cells (34,35). Until relatively recently, the former mechanism was thought to predominate, and, indeed, certain acquired drug-resistant states are clearly associated with the loss of membrane proteins which can be shown to bind and transport agents into cells (34). However, other resistant states have been shown to be associated with the acquisition of membrane transport proteins which remove toxins (and, therefore, chemotherapeutic agents) both from normal and malignant cells. 

Fig. 3. Possible interactions between PKC and MDRl-mediated drug resistance. Activation of PKC might activate the drug efflux by phosphorylation of PGP (A), induce or activate proteins which modulate PGP (B, Castro et al., 1999), or induce the transcription and translation of MDRl-mRNA (C). Inhibitors of PKC might prevent phosphorylation of PGP leading to a decrease the drug efflux (D). inhibit the efflux of drugs by direct interaction with the drug binding site(s) or the ATP-binding sites of PGP (E), or prevent the expression of MDRl-mRNA (F)...

Smyth MJ, Drasovskis E, Sutton VR, Johnstone RW (1998) The drug efflux protein, P-glycoprotein, additionally protects drug-resistant tumor cells from multiple forms of caspase-dependent apoptosis. Proc Natl Acad Sd USA 95 7024-7029... 

Zaman, G.J., et al. 1994. The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. Proc Natl Acad Sci 91 8822. 

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