Role of multidrug resistance-associated protein 1 in the pathogenesis of allergic airway inflammation

Yoshioka, Masahiro; Sagara, Hironori; Takahashi, Fumiyuki; Harada, Norihiro; Nishio, Kazuto; Mori, Akio; Ushio, Hiroko; Shimizu, Kazuharu; Okada, Takenori; Ota, Masaho; Ito, Yoichi M.; Nagashima, Osamu; Atsuta, Ryo; Suzuki, Toshihiro; Fukuda, Takeshi; Fukuchi, Yoshinosuke; Takahashi, Kazuhisa

doi:10.1152/ajplung.00026.2008

Cited by 21 publications

(15 citation statements)

References 30 publications

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“…Studies in Abcc1 Ϫ/Ϫ mice confirmed that LTC 4 was a physiologically relevant substrate as these animals exhibited decreased inflammatory responses consistent with impaired LTC 4 export (17). It was suggested that MRP1 inhibitors might be developed that could be useful in the treatment of inflammatory disorders, including those involving the airways such as asthma and chronic obstructive pulmonary disease (17,23). Unfortunately, this has not turned out to be the case.…”

Section: Lipid-derived Signaling Molecules As Substrates Of Mrp1mentioning

confidence: 99%

“…Thus, MRP1 may play a part in inflammatory and other immunological diseases, age-related macular degeneration, cardiovascular disease, and certain neurological disorders as well as tumor progression (4,(22)(23)(24)(25)(26)(27)(28). This potentially broader role of MRP1 in human health and disease has occurred in conjunction with a growing appreciation of its ability to mediate the efflux of bioactive OAs and regulating oxidative stress (25, 29 -31).…”

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confidence: 99%

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Multidrug Resistance Protein 1 (MRP1, ABCC1), a “Multitasking” ATP-binding Cassette (ABC) Transporter

Cole

2014

Journal of Biological Chemistry

300

245

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The multidrug resistance protein 1 (MRP1) encoded by ABCC1 was originally discovered as a cause of multidrug resistance in tumor cells. However, it is now clear that MRP1 serves a broader role than simply mediating the ATP-dependent efflux of drugs from cells. The antioxidant GSH and the pro-inflammatory cysteinyl leukotriene C 4 have been identified as key physiological organic anions effluxed by MRP1, and an ever growing body of evidence indicates that additional lipid-derived mediators are also substrates of this transporter. As such, MRP1 is a multitasking transporter that likely influences the etiology and progression of a host of human diseases.

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Section: Lipid-derived Signaling Molecules As Substrates Of Mrp1mentioning

confidence: 99%

mentioning

confidence: 99%

Multidrug Resistance Protein 1 (MRP1, ABCC1), a “Multitasking” ATP-binding Cassette (ABC) Transporter

Cole

2014

Journal of Biological Chemistry

300

245

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“…Although Mrp1 2/2 mice have normal fertility and viability, their ability to transport key endo-and xenobiotics is compromised. Thus, Mrp1 2/2 mice are hypersensitive to the anticancer drug etoposide and exhibit reduced inflammatory responses attributed to disrupted leukotriene homeostasis caused by the inability to efflux leukotriene C4 (Wijnholds et al, 1997;Yoshioka et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

Loss of Multidrug Resistance–Associated Protein 1 Potentiates Chronic Doxorubicin-Induced Cardiac Dysfunction in Mice

Zhang

Deng

Sunkara

et al. 2015

J Pharmacol Exp Ther

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Doxorubicin (DOX), an effective cancer chemotherapeutic agent, induces dose-dependent cardiotoxicity, in part due to its ability to cause oxidative stress. We investigated the role of multidrug resistance-associated protein 1 (Mrp1/Abcc1) in DOX-induced cardiotoxicity in C57BL wild-type (WT) mice and their Mrp1 null (Mrp1 2/2 ) littermates. Male mice were administered intraperitoneal DOX (3 or 2 mg/kg body weight) or saline twice a week for 3 weeks and examined 2 weeks after the last dose (protocol A total dose: 18 mg/kg) or for 5 weeks, and mice were examined 48 hours and 2 weeks after the last dose (protocol B total dose: 20 mg/kg). Chronic DOX induced body weight loss and hemotoxicity, adverse effects significantly exacerbated in Mrp1 2/2 versus WT mice. In the heart, significantly higher basal levels of glutathione (1.41-fold 6 0.27-fold) and glutathione disulfide (1.35-fold 6 0.16-fold) were detected in Mrp1 2/2 versus WT mice, and there were comparable decreases in the glutathione/glutathione disulfide ratio in WT and Mrp1 2/2 mice after DOX administration. Surprisingly, DOX induced comparable increases in 4-hydroxynonenal glutathione conjugate concentration in hearts from WT and Mrp1 2/2 mice. However, more DOX-induced apoptosis was detected in Mrp1 2/2 versus WT hearts (P , 0.05) (protocol A), and cardiac function, assessed by measurement of fractional shortening and ejection fraction with echocardiography, was significantly decreased by DOX in Mrp1 2/2 versus WT mice (P , 0.05; 95% confidence intervals of 20.0%-24.3% versus 23.7%-29.5% for fractional shortening, and 41.5%-48.4% versus 47.7%-56.7% for ejection fraction; protocol B). Together, these data indicate that Mrp1 protects the mouse heart against chronic DOX-induced cardiotoxicity.

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“…It also transports GSH in both its antioxidant and prooxidant (glutathione disulfide) states. Physiologic roles for MRP1 have been established, not only by its ability to modulate GSH homeostasis (Ballatori et al, 2009;Cole, 2013) but also by the characterization of Abcc1 2/2 mice which exhibit impaired inflammatory responses attributed to disrupted leukotriene homeostasis (Wijnholds et al, 1997;Yoshioka et al, 2009). Single-nucleotide polymorphisms (SNPs) are common in genes encoding proteins involved in drug metabolism and transport, and interindividual differences can contribute to differences in absorption, distribution, and elimination that ultimately affect drug efficacy and toxicity (Kroetz et al, 2010;Ieiri, 2012).…”

Section: Introductionmentioning

confidence: 99%

Two Polymorphic Variants ofABCC1Selectively Alter Drug Resistance and Inhibitor Sensitivity of the Multidrug and Organic Anion Transporter Multidrug Resistance Protein 1

Conseil

Cole

2013

Drug Metab Dispos

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In this study we compared the in silico predictions of the effect of ABCC1 nonsynonymous single nucleotide polymorphisms (nsSNPs) with experimental data on MRP1 transport function and response to chemotherapeutics and multidrug resistance protein 1 (MRP1) inhibitors. Vectors encoding seven ABCC1 nsSNPs were stably expressed in human embryonic kidney (HEK) cells, and levels and localization of the mutant MRP1 proteins were determined by confocal microscopy and immunoblotting. The function of five of the mutant proteins was determined using cell-based drug and inhibitor sensitivity and efflux assays, and membrane-based organic anion transport assays. Predicted consequences of the mutations were determined by multiple bioinformatic methods. Mutants C43S and S92F were correctly routed to the HEK cell plasma membrane, but the levels were too low to permit functional characterization. In contrast, levels and membrane trafficking of R633Q, G671V, R723Q, A989T, and C1047S were similar to wild-type MRP1. In cell-based assays, all five mutants were equally effective at effluxing calcein, but only two exhibited reduced resistance to etoposide (C1047S) and vincristine (A989T; C1047S). The GSH-dependent inhibitor quinolin-5-yl)-cyclohexylmethyl]-benzamide)] was less effective at blocking calcein efflux by A989T, but in a membrane-based assay, organic anion transport by A989T and C1047S was inhibited by MRP1 modulators as well as wild-type MRP1. GSH accumulation assays suggest cellular GSH efflux by A989T and C1047S may be impaired. In conclusion, although six in silico analyses consistently predict deleterious consequences of ABCC1 nsSNPs G671V, changes in drug resistance and inhibitor sensitivity were only observed for A989T and C1047S, which may relate to GSH transport differences.

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Role of multidrug resistance-associated protein 1 in the pathogenesis of allergic airway inflammation

Abstract: of multidrug resistance-associated protein 1 in the pathogenesis of allergic airway inflammation.

Cited by 21 publications

References 30 publications

Multidrug Resistance Protein 1 (MRP1, ABCC1), a “Multitasking” ATP-binding Cassette (ABC) Transporter

Multidrug Resistance Protein 1 (MRP1, ABCC1), a “Multitasking” ATP-binding Cassette (ABC) Transporter

Loss of Multidrug Resistance–Associated Protein 1 Potentiates Chronic Doxorubicin-Induced Cardiac Dysfunction in Mice

Two Polymorphic Variants ofABCC1Selectively Alter Drug Resistance and Inhibitor Sensitivity of the Multidrug and Organic Anion Transporter Multidrug Resistance Protein 1

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