Null alleles of ABCG2 encoding the breast cancer resistance protein define the new blood group system Junior

Saison, Carole; Helias, Virginie; Ballif, Bryan A.; Peyrard, Thierry; Puy, Hervé; Miyazaki, Tôru; Perrot, S.; Vayssier‐Taussat, Muriel; Waldner, Mauro; Pennec, Pierre‐Yves Le; Cartron, Jean‐Pierre; Arnaud, Lionel

doi:10.1038/ng.1070

Cited by 104 publications

(154 citation statements)

References 28 publications

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“…There are even substantial numbers of individuals with partial or complete genetic deficiencies in BCRP [e.g., Jr(a-) individuals] (Saison et al, 2012) or in MRP2 (Dubin-Johnson syndrome). Since PhIP is an abundant carcinogen, it will be of interest to assess the effect of such ABC transporter deficiencies on the carcinogenic potential of PhIP in epidemiologic studies.…”

Section: Discussionmentioning

confidence: 99%

Bcrp1;Mdr1a/b;Mrp2 Combination Knockout Mice: Altered Disposition of the Dietary Carcinogen PhIP (2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine) and Its Genotoxic Metabolites

et al. 2013

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The multidrug transporters breast cancer resistance protein (BCRP), multidrug-resistance protein 1 (MDR1), and multidrugresistance-associated protein (MRP) 2 and 3 eliminate toxic compounds from tissues and the body and affect the pharmacokinetics of many drugs and other potentially toxic compounds. The food-derived carcinogen PhIP (2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine) is transported by BCRP, MDR1, and MRP2. To investigate the overlapping functions of Bcrp1, Mdr1a/b, and Mrp2 in vivo, we generated Bcrp1;Mdr1a/b;Mrp2 2/2 mice, which are viable and fertile. These mice, together with Bcrp1;Mrp2;Mrp3 2/2 mice, were used to study the effects of the multidrug transporters on the pharmacokinetics of PhIP and its metabolites. Thirty minutes after oral or intravenous administration of PhIP (1 mg/kg), the PhIP levels in the small intestine were reduced 4-to 6-fold in Bcrp1;Mdr1a/b;Mrp2 2/ 2 and Bcrp1;Mrp2;Mrp3 2/2 mice compared with wild-type mice. Fecal excretion of PhIP was reduced 8-to 20-fold in knockouts. Biliary PhIP excretion was reduced 41-fold in Bcrp1;Mdr1a/b;Mrp2 2/2 mice. Biliary and small intestine levels of PhIP metabolites were reduced in Bcrp1;Mrp2-deficient mice. Furthermore, in both knockout strains, kidney levels and urinary excretion of genotoxic PhIPmetabolites were significantly increased, suggesting that reduced biliary excretion of PhIP and PhIP metabolites leads to increased urinary excretion of these metabolites and increased systemic exposure. Bcrp1 and Mdr1a limited PhIP brain accumulation. In Bcrp1;Mrp2;Mrp3 2/2 , but not Bcrp1; Mdr1a/b;Mrp 2/2 mice, the carcinogenic metabolites N2-OHPhIP (2-hydroxyamino-1-methyl-6-phenylimidazo [4,5-b]pyridine) and PhIP-5-sulfate (a genotoxicity marker) accumulated in liver tissue, indicating that Mrp3 is involved in the sinusoidal secretion of these compounds. We conclude that Bcrp1, Mdr1a/b, Mrp2, and Mrp3 significantly affect tissue disposition and biliary and fecal elimination of PhIP and its carcinogenic metabolites and may affect PhIP-induced carcinogenesis as a result.

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Section: Discussionmentioning

confidence: 99%

Bcrp1;Mdr1a/b;Mrp2 Combination Knockout Mice: Altered Disposition of the Dietary Carcinogen PhIP (2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine) and Its Genotoxic Metabolites

et al. 2013

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“…Lastly, it has recently been shown that ABCG2 null alleles define a new blood type, the Jr(a-) blood type, and red blood cells from the individuals with the Jr(a-) blood type do not express BCRP (176). However, the Jr(a-) individuals with ABCG2 null alleles appear phenotypically normal (176).…”

Section: In Bcrp1mentioning

confidence: 99%

“…However, the Jr(a-) individuals with ABCG2 null alleles appear phenotypically normal (176). The role of BCRP in determining the Jr(a-) blood type and pharmacological implications of this observation are currently not known.…”

Section: In Bcrp1mentioning

confidence: 99%

Role of the Breast Cancer Resistance Protein (BCRP/ABCG2) in Drug Transport—an Update

Mao

Unadkat

2014

AAPS J

519

387

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Abstract. The human breast cancer resistance protein (BCRP, gene symbol ABCG2) is an ATP-binding cassette (ABC) efflux transporter. It was so named because it was initially cloned from a multidrugresistant breast cancer cell line where it was found to confer resistance to chemotherapeutic agents such as mitoxantrone and topotecan. Since its discovery in 1998, the substrates of BCRP have been rapidly expanding to include not only therapeutic agents but also physiological substances such as estrone-3-sulfate, 17β-estradiol 17-(β-D-glucuronide) and uric acid. Likewise, at least hundreds of BCRP inhibitors have been identified. Among normal human tissues, BCRP is highly expressed on the apical membranes of the placental syncytiotrophoblasts, the intestinal epithelium, the liver hepatocytes, the endothelial cells of brain microvessels, and the renal proximal tubular cells, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds as well as tissue protection against xenobiotic exposure. As a result, BCRP has now been recognized by the FDA to be one of the key drug transporters involved in clinically relevant drug disposition. We published a highly-accessed review article on BCRP in 2005, and much progress has been made since then. In this review, we provide an update of current knowledge on basic biochemistry and pharmacological functions of BCRP as well as its relevance to drug resistance and drug disposition.

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“…Polymorphic forms of ABCG2 are associated with gout because of decreased excretion of uric acid in the proximal tubule of the kidney (Woodward et al, 2009). It was recently recognized that healthy individuals of the Jr(a 2 ) blood type carry two null alleles of ABCG2 despite the important physiologic role understood for ABCG2 (Saison et al, 2012;Zelinski et al, 2012). The functional consequences of ABCG2 loss are still unknown but are not associated with obvious disease.…”

Section: Introductionmentioning

confidence: 99%

Overlapping Substrate and Inhibitor Specificity of Human and Murine ABCG2

Bakhsheshian¹,

Hall²,

Robey³

et al. 2013

Drug Metab Dispos

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ABCG2 (also known as breast cancer resistance protein) is an ATP-binding cassette (ABC) transporter localized to the plasma membrane where it mediates the efflux of xenobiotics, including potential therapeutics. Studies investigating Abcg2 function at the blood-brain barrier in mouse models are often compared with human ABCG2 function. It is critical to understand the nature of species differences between mouse and human ABCG2, since extrapolations are made from murine data to humans. Two independent drug-selected cell line pairs expressing human or mouse ABCG2 were compared for efflux of fluorescent substrates using flow cytometry. To this end, we developed and characterized a new mouse Abcg2-expressing subline that demonstrated efflux of known fluorescent ABCG2 substrates and increased resistance to mitoxantrone, which is reduced in the presence of the ABCG2 inhibitor Ko143. Our results indicate that the substrate specificity of human and mouse ABCG2 is very similar. We identified a new human and mouse ABCG2 substrate, a porphyrin analog, purpurin-18 (Pp-18), which is not a substrate for P-glycoprotein or multidrug resistance protein 1. The ability of inhibitors to block efflux activity of ABCG2 was assessed using Pp-18. Inhibitors also demonstrated similar effects on human and mouse ABCG2. Chrysin, benzoflavone, and cyclosporin A inhibited Pp-18 efflux in both human and mouse ABCG2. The similarity of the substrate and inhibitor specificity of human and mouse ABCG2 supports interpretation of mouse models in understanding the clinical, pharmacological, and physiologic roles of ABCG2.

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Null alleles of ABCG2 encoding the breast cancer resistance protein define the new blood group system Junior

Cited by 104 publications

References 28 publications

Bcrp1;Mdr1a/b;Mrp2 Combination Knockout Mice: Altered Disposition of the Dietary Carcinogen PhIP (2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine) and Its Genotoxic Metabolites

Bcrp1;Mdr1a/b;Mrp2 Combination Knockout Mice: Altered Disposition of the Dietary Carcinogen PhIP (2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine) and Its Genotoxic Metabolites

Role of the Breast Cancer Resistance Protein (BCRP/ABCG2) in Drug Transport—an Update

Overlapping Substrate and Inhibitor Specificity of Human and Murine ABCG2

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