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Catalog > Transporters > BCRP

BCRP

BCRP transporter (ATP Binding Cassette Protein G2 /ABCG2)

ABCG2, more commonly referred to as BCRP (Breast Cancer Resistant Protein) plays an important role in drug disposition and distribution, similar to P-gp.  BCRP is an efflux transporter that prevents drugs from penetrating tissues such as the brain, gut, and tumors and is also involved in biliary excretion and to some extent, renal excretion of drugs. Current FDA and EMA recommendations for testing BCRP are based mainly on its role in intestinal absorption. Drugs that are substrates of BCRP have the potential to be victims to drug drug interactions (DDI) when this transporter is inhibited. This is especially true for drugs with a narrow therapeutic index and low oral bioavailability.

Localization

BCRP is highly expressed in tissue barriers such as the colon, small intestine, blood-brain barrier (BBB), placenta and liver canalicular membrane, indicating a role in barrier function.  In polarized cells of the gut, kidney and liver epithelium, BCRP is localized to the apical membrane where it mediates unidirectional transport of substrates to the luminal side of the organ acting as an efflux pump [1].

Function, physiology and clinically significant polymorphisms

BCRP transporter is a 72 kDa „half transporter” encoded by the ABCG2 gene, consisting of six transmembrane domains and functions as a homodimer or homotetramer [2]. 

The physiological functions of BCRP transporter include regulation of intestinal absorption, biliary and renal secretion of substrates and protection of the fetus and brain from toxins. BCRP is associated with resistance to a range of anticancer agents and is expressed in hematological malignancies and solid tumors, indicating a role in clinical drug resistance of cancers.  BCRP presents uptake resistance to various xenobiotics and cytotoxic agents, thereby influencing the disposition of structurally unrelated compounds from different therapeutic classes throughout the body. 

BCRP substrates include diverse drugs (glyburide, nitrofurantoin, dipyridamole, cimetidine,  chlorothiazide and sulfasalazine, leflunomide), chemotherapeutic agents, dietary (porphyrins) and endogenous (e.g. estrones, bile acids) compounds [3-5].  The overlap in substrate specificity between BCRP and MDR1 (e.g. for glyburide, imatinib, methotrexate, mitoxantrone and prazosin) increases the barrier function of the efflux transporters [6, 7].  While MDR1 generally transports hydrophobic compounds, BCRP additionally transports hydrophilic conjugated organic anions, particularly the sulfates, with a high affinity.

BCRP inhibitors may be highly potent and relatively specific (e.g. fumitremorgin C and its analog Ko143), highly potent and relatively non-specific (e.g.  GF120819, which is also an MDR1 inhibitor) and more general inhibitors such as cyclosporine A and some of the anti-HIV protease inhibitors.  Inhibition of BCRP can cause significant PK changes e.g. the oral bioavailability of topotecan (substrate) more than doubles after co-administration with GF120918 (inhibitor)[8].  Bcrp1-knockout mice have 111 times higher systemic exposure of sulfasalazine after oral administration, as compared with wild-type mice [9].

Over 80 single-nucleotide polymorphisms are reported in the BCRP transporter gene, although few modify transport activity.  The non-synonymous SNP, e5/C421A is associated with lower BCRP expression, as the protein is less stable and has reduced plasma membrane localization [10].  Q141K is found at high allele frequencies (30 –60%) in Japanese and Chinese populations and at relatively low allele frequencies (5 – 10%) in Caucasians and African-Americans. Clinically, this variant is associated with higher plasma levels of BCRP substrate drugs such as topotecan, rosuvastatin, sulfasalazine, diflomotecan,  imatinib, atorvastatin and methotrexate [11, 12] but not of irinotecan, pitavastatin and lamivudine [13].  Porphyrin transport is affected by the variants Q126stop, F208S, S248P, E334stop and S441N.

The nuclear receptors PXR, CAR and AhR regulate BCRP transporter expression, in response to treatment with xenobiotics such as rifampicin, phenobarbital and TCDD [14].

Clinical significance

BCRP actively transports xenobiotics including anticancer drugs and restricts the uptake of substrates from the gut lumen and through the BBB.  BCRP expression in cancer cells confers drug- resistance in leukemia and higher levels are reported in solid tumors from the digestive tract, endometrium, lung and melanoma [15], although, contrarily, expression is generally low in breast cancer tumors [16]. There is significant association between BCRP expression and tumor response to chemotherapy and progression-free survival [17].  BCRP is implicated in mitoxantrone efflux in 70% of the patients studied, despite very low mRNA levels [18].  The placenta has high BCRP expression and this and is believed to protect the fetus e.g. the antidiabetic drug, glyburide has limited fetal penetration due to efflux by BCRP. In Abcg2 deficient pregnant mice co-administered topotecan (substrate) and GF120918 (inhibitor), the fetal plasma contained twice the levels of topotecan as the mothers [19].  In the liver, BCRP plays a major role in the biliary excretion but a minor role in the intestinal transport of troglitazone sulfate [20].  Although BCRP transports bile salts, this is believed to be mainly from the intestine and kidney, with a relatively minor role in the liver [21]. 

Regulatory Requirements

BCRP has relevance to drug PK and interactions, for BBB and tumor penetration and is required evaluated in vitro, by the regulatory agencies FDA and EMA for all drug candidates prior to going to market.  Drug candidates need to be screened for in vitro BCRP substrate and inhibition liability and based on this data, decisions are made for the need for BCRP transporter – based clinical drug interaction trials. 

Location
Endogenous substrates
Substrates used experimentally
Substrate drugs
Inhibitors
Intestinal enterocytes, hepatocytes: canalicular membran, kidney proximal tubule, brain endothelia, placenta, stem cells, mammary glands
dietary flavonoids, porphyrins, estrone 3-sulfate
Fluorophores such as rhodamine 123 and Hoechst 33342, Conjugates such as estrone-3-sulfate and E217ßG
Anthracyclines, daunorubicin, doxorubicin, topotecan, SN-38, irinotecan, methotrexate, imatinib, irinotecan, Mitoxantrone, nucleoside analogs, prazosin, pantoprazole, statins, topotecan
Fumitremorgin C, Ko132, Ko134, Iressa, Imatinib mesylate, novobiocin, estrone, 17ß-estradiol, ritonavir, omeprazole, ivermectin [22]

References

  1. Maliepaard, M., et al., Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res, 2001. 61(8): p. 3458-64.
  2. Kage, K., et al., Dominant-negative inhibition of breast cancer resistance protein as drug efflux pump through the inhibition of S-S dependent homodimerization. Int J Cancer, 2002. 97(5): p. 626-30.
  3. Beery, E., et al., ABCG2 modulates chlorothiazide permeability in vitro - characterization of the interaction. Drug Metab Pharmacokinet, 2011.
  4. Jani, M., et al., Kinetic characterization of sulfasalazine transport by human ATP-binding cassette G2. Biol Pharm Bull, 2009. 32(3): p. 497-9.
  5. Kis, E., et al., Leflunomide and its metabolite A771726 are high affinity substrates of BCRP: implications for drug resistance. Ann Rheum Dis, 2009. 68(7): p. 1201-7.
  6. Kodaira, H., et al., Kinetic analysis of the cooperation of P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp/Abcg2) in limiting the brain and testis penetration of erlotinib, flavopiridol, and mitoxantrone. J Pharmacol Exp Ther, 2010. 333(3): p. 788-96.
  7. Polli, J.W., et al., An unexpected synergist role of P-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethy l]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016). Drug Metab Dispos, 2009. 37(2): p. 439-42.
  8. Kruijtzer, C.M., et al., Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J Clin Oncol, 2002. 20(13): p. 2943-50.
  9. Zaher, H., et al., Breast cancer resistance protein (Bcrp/abcg2) is a major determinant of sulfasalazine absorption and elimination in the mouse. Mol Pharm, 2006. 3(1): p. 55-61.
  10. Furukawa, T., et al., Major SNP (Q141K) Variant of Human ABC Transporter ABCG2 Undergoes Lysosomal and Proteasomal Degradations. Pharm Res, 2008.
  11. Keskitalo, J.E., et al., ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther, 2009. 86(2): p. 197-203.
  12. Warren, R.B., et al., Genetic variation in efflux transporters influences outcome to methotrexate therapy in patients with psoriasis. J Invest Dermatol, 2008. 128(8): p. 1925-9.
  13. Ieiri, I., et al., SLCO1B1 (OATP1B1, an uptake transporter) and ABCG2 (BCRP, an efflux transporter) variant alleles and pharmacokinetics of pitavastatin in healthy volunteers. Clin Pharmacol Ther, 2007. 82(5): p. 541-7.
  14. Jigorel, E., et al., Differential regulation of sinusoidal and canalicular hepatic drug transporter expression by xenobiotics activating drug-sensing receptors in primary human hepatocytes. Drug Metab Dispos, 2006. 34(10): p. 1756-63.
  15. Diestra, J.E., et al., Frequent expression of the multi-drug resistance-associated protein BCRP/MXR/ABCP/ABCG2 in human tumours detected by the BXP-21 monoclonal antibody in paraffin-embedded material. J Pathol, 2002. 198(2): p. 213-9.
  16. Robey, R.W., et al., ABCG2: determining its relevance in clinical drug resistance. Cancer Metastasis Rev, 2007. 26(1): p. 39-57.
  17. Kim, Y.H., et al., Expression of breast cancer resistance protein is associated with a poor clinical outcome in patients with small-cell lung cancer. Lung Cancer, 2008.
  18. Suvannasankha, A., et al., Breast cancer resistance protein (BCRP/MXR/ABCG2) in adult acute lymphoblastic leukaemia: frequent expression and possible correlation with shorter disease-free survival. Br J Haematol, 2004. 127(4): p. 392-8.
  19. Jonker, J.W., et al., Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J Natl Cancer Inst, 2000. 92(20): p. 1651-6.
  20. Enokizono, J., H. Kusuhara, and Y. Sugiyama, Involvement of breast cancer resistance protein (BCRP/ABCG2) in the biliary excretion and intestinal efflux of troglitazone sulfate, the major metabolite of troglitazone with a cholestatic effect. Drug Metab Dispos, 2007. 35(2): p. 209-14.
  21. Mennone, A., et al., Role of breast cancer resistance protein in the adaptive response to cholestasis. Drug Metab Dispos, 2010. 38(10): p. 1673-8.
  22. Jani, M., et al., Ivermectin interacts with human ABCG2. J Pharm Sci, 2011. 100(1): p. 94-7.

 

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