Natural Allelic Variants of Bovine ATP-Binding Cassette Transporter ABCG2: Increased Activity of the Ser581 Variant and Development of Tools for the Discovery of New ABCG2 Inhibitors

Merino, Gracia; Real, Rebeca; Baro, Marta; González-Lobato, Lucía; Prieto, J. E.; Alvarez, Ana I.; Marques, Margarita M

doi:10.1124/dmd.108.022715

Cited by 24 publications

(28 citation statements)

References 27 publications

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“…The greater capacity to transfer danofloxacin into milk in the Y/S heterozygous animals indicates that Y581S SNP significantly affects the secretion of this antibiotic into milk. Our findings are in agreement with our previously published in vitro data showing the greater in vitro capacity of the S581 variant compared with the Y581 variant in terms of higher relative V max values (Merino et al, 2009). Moreover, we recently reported a higher danofloxacin transport ratio in cells transduced with the S581 variant in comparison with Y581 cells (Real et al, 2011a).…”

Section: Resultssupporting

confidence: 83%

“…In addition, a correlation has been suggested between this SNP and fertility (Komisarek and Dorynek, 2009). With regard to the effect of this SNP on drug transport, our previous in vitro results described the Y581S SNP as a gain-of-function polymorphism, showing a lower mitoxantrone accumulation in ovine primary fibroblast transiently transfected with the S581 variant, when compared with the Y581 variant (Merino et al, 2009). Recently, the greater activity of the S581 allele was confirmed on transepithelial transport of antibiotics using stably transduced cell models (Real et al, 2011a).…”

Section: Introductionmentioning

confidence: 99%

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The Bovine ATP-Binding Cassette Transporter ABCG2 Tyr581Ser Single-Nucleotide Polymorphism Increases Milk Secretion of the Fluoroquinolone Danofloxacin

et al. 2012

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The bovine adenosine triphosphate-binding cassette transporter G2 (ABCG2/breast cancer resistance protein) polymorphism Tyr581Ser (Y581S) has recently been shown to increase in vitro transepithelial transport of antibiotics. Since this transporter has been extensively related to the active secretion of drugs into milk, the potential in vivo effect of this polymorphism on secretion of xenobiotics in livestock could have striking consequences for milk production, the dairy industry, and public health. Our purpose was to study the in vivo effect of this polymorphism on the secretion of danofloxacin, a widely used veterinary antibiotic, into milk. Danofloxacin (1.25 mg/kg) was administered to six Y/Y 581 homozygous and six Y/S 581 heterozygous lactating cows, and plasma and milk samples were collected and analyzed by high-performance liquid chromatography. No differences were found in the pharmacokinetic parameters of danofloxacin in plasma between the two groups of animals. In contrast, Y/S heterozygous cows showed a 2-fold increase in danofloxacin levels in milk. In addition, the pharmacokinetic elimination parameters, mean residence time and elimination half-life, were significantly lower in the milk of the animals carrying the Y/S polymorphism. These in vivo results are in agreement with our previously published in vitro data, which showed a greater capacity of the S581 variant in accumulation assays, and demonstrate, for the first time, an important effect of the Y581S single-nucleotide polymorphism on antibiotic secretion into cow milk. These findings could be extended to other ABCG2 substrates, and may be relevant for the treatment of mastitis and for the design of accurate and novel strategies to handle milk residues. IntroductionThe ATP-binding cassette (ABC) transporter ABCG2 (breast cancer resistance protein) is expressed in a wide range of tissues and organs, including the intestine, liver, blood-brain barrier, and mammary gland (van Herwaarden and Schinkel, 2006). It affects the bioavailability of its substrates and mediates the active secretion of xenobiotics and several vitamins in milk (van Herwaarden et al., 2007). The occurrence of drug residues in milk could lead to the development of bacterial resistance, allergies, or hypersensitivity reactions in consumers (McManaman and Neville, 2003). On the other hand, effective treatments for mastitis may require a considerable transfer of drugs into milk (Escudero et al., 2007). All of these issues are of great concern for general public health, the dairy industry, and veterinary therapeutics. Hence, identification of relevant factors for the transfer of drugs into milk in livestock constitutes a priority.Changes in the expression and/or the function of ABCG2 can lead to dramatic variations in the pharmacokinetics and secretion of its substrates into milk Ni et al., 2010). Several single-nucleotide polymorphisms (SNPs) have been studied in human ABCG2, and of these, Gln141Lys (Q141K) is one of the most important, causing impaired urate transport wh...

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Section: Resultssupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

The Bovine ATP-Binding Cassette Transporter ABCG2 Tyr581Ser Single-Nucleotide Polymorphism Increases Milk Secretion of the Fluoroquinolone Danofloxacin

et al. 2012

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“…The Y581S variant was inhibited but to a lesser extent probably due to its higher transport capacity. This finding agrees with a previous report in which some compounds differentially inhibited both variants of bovine ABCG2 (Merino et al, 2009). …”

Section: Enterolactonesupporting

confidence: 94%

Effect of bovine ABCG2 polymorphism Y581S SNP on secretion into milk of enterolactone, riboflavin and uric acid

Otero

Miguel

González-Lobato

et al. 2016

animal

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The ATP-binding cassette transporter G2/breast cancer resistance protein (ABCG2/BCRP) is an efflux protein involved in the bioavailability and milk secretion of endogenous and exogenous compounds, actively affecting milk composition. A limited number of physiological substrates have been identified. However, no studies have reported the specific effect of this polymorphism on the secretion into milk of compounds implicated in milk quality such as vitamins or endogenous compounds. The bovine ABCG2 Y581S polymorphism is described as a gain-of-function polymorphism that increases milk secretion and decreases plasma levels of its substrates. This work aims to study the impact of Y581S polymorphism on plasma disposition and milk secretion of compounds such as riboflavin (vitamin B 2 ), enterolactone, a microbiota-derived metabolite from the dietary lignan secoisolariciresinol and uric acid. In vitro transport of these compounds was assessed in MDCK-II cells overexpressing the bovine ABCG2 (WT-bABCG2) and its Y581S variant (Y581S-bABCG2). Plasma and milk levels were obtained from Y/Y homozygous and Y/S heterozygous cows. The results show that riboflavin was more efficiently transported in vitro by the Y581S variant, although no differences were noted in vivo. Both uric acid and enterolactone were substrates in vitro of the bovine ABCG2 variants and were actively secreted into milk with a two-fold increase in the milk/plasma ratio for Y/S with respect to Y/Y cows. The in vitro ABCG2-mediated transport of the drug mitoxantrone, as a model substrate, was inhibited by enterolactone in both variants, suggesting the possible in vivo use of this enterolignan to reduce ABCG2-mediated milk drug transfer in cows. The Y581S variant was inhibited to a lesser extent probably due to its higher transport capacity. All these findings point to a significant role of the ABCG2 Y581S polymorphism in the milk disposition of enterolactone and the endogenous molecules riboflavin and uric acid, which could affect both milk quality and functionality.

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“…The natural variant of bovine ABCG2, Y581S, at position 581 within TM5 also showed a 1.4-fold increase in MX efflux (Merino et al, 2009). It is worth noting that K452A and H457A are not selected during evolution.…”

mentioning

confidence: 99%

Role of Basic Residues within or near the Predicted Transmembrane Helix 2 of the Human Breast Cancer Resistance Protein in Drug Transport

Cai¹,

Bikádi²,

Ni³

et al. 2010

J Pharmacol Exp Ther

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The human breast cancer resistance protein (BCRP/ABCG2) mediates efflux of drugs and xenobiotics out of cells. In this study, we investigated the role of five basic residues within or near transmembrane (TM) 2 of BCRP in transport activity. Lys , and Lys 473 were replaced with Ala or Asp. K452A, K453D, H457A, R465A, and K473A were stably expressed in human embryonic kidney (HEK) cells, and their plasma membrane expression and transport activities were examined. All of the mutants were expressed predominantly on the plasma membrane of HEK cells. After normalization to BCRP levels, the activities of K452A and H457A in effluxing mitoxantrone, boron-dipyrromethene-prazosin, and Hoechst33342 were increased approximately 2-to 6-fold compared with those of wild-type BCRP, whereas the activities of K453D and R465A were decreased by 40 to 60%. Likewise, K452A and H457A conferred increased resistance to mitoxantrone and 7-ethyl-10-hydroxy-camptothecin (SN-38), and K453D and R465A exhibited lower resistance. The transport activities and drug-resistance profiles of K473A were not changed. These mutations also differentially affected BCRP ATPase activities with a 2-to 4-fold increase in V max /K m for K452A and H457A and a 40 to 70% decrease for K453D and R465A. These mutations may induce conformational changes as manifested by the altered binding of the 5D3 antibody to BCRP in the presence of prazosin and altered trypsin digestion. Molecular modeling and docking calculations indicated that His 457 and Arg 465 might be directly involved in substrate binding. In conclusion, we have identified several basic residues within or near TM2 that may be important for interaction of substrates with BCRP.

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Natural Allelic Variants of Bovine ATP-Binding Cassette Transporter ABCG2: Increased Activity of the Ser581 Variant and Development of Tools for the Discovery of New ABCG2 Inhibitors

Cited by 24 publications

References 27 publications

The Bovine ATP-Binding Cassette Transporter ABCG2 Tyr581Ser Single-Nucleotide Polymorphism Increases Milk Secretion of the Fluoroquinolone Danofloxacin

The Bovine ATP-Binding Cassette Transporter ABCG2 Tyr581Ser Single-Nucleotide Polymorphism Increases Milk Secretion of the Fluoroquinolone Danofloxacin

Effect of bovine ABCG2 polymorphism Y581S SNP on secretion into milk of enterolactone, riboflavin and uric acid

Role of Basic Residues within or near the Predicted Transmembrane Helix 2 of the Human Breast Cancer Resistance Protein in Drug Transport

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