A new aspect on glutathione-associated biological function of MRP/GS-X pump and its gene expression

Ishikawa, Toshihisa; Kuo, M. Tien; Furuta, Kyoji; Suzuki, Masaaki

doi:10.1007/978-94-017-2374-9_5

Cited by 3 publications

(3 citation statements)

References 39 publications

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“…Indeed, apart from two mammalian members of the organic anion transporting polypeptide (OATP or SLC21A) family (12,13), all glutathione and glutathione S-conjugate exporters identified in bacteria, yeast, and mammalian cells belong to the multidrug resistance protein/cystic fibrosis transmembrane conductance regulator superfamily and are characterized by diverse substrate specificities. For instance, human MRP1 and MRP2 export glutathione conjugates and GSH (14,15), whereas the Escherichia coli CydDC exports cysteine and GSH (16).…”

mentioning

confidence: 99%

Glutathione import in Haemophilus influenzae Rd is primed by the periplasmic heme-binding protein HbpA

Vergauwen

Elegheert

Dansercoer

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

104

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Glutathione (GSH) is a vital intracellular cysteine-containing tripeptide across all kingdoms of life and assumes a plethora of cellular roles. Such pleiotropic behavior relies on a finely tuned spatiotemporal distribution of glutathione and its conjugates, which is not only controlled by synthesis and breakdown, but also by transport. Here, we show that import of glutathione in the obligate human pathogen Haemophilus influenzae , a glutathione auxotrophe, is mediated by the ATP-binding cassette (ABC)-like dipeptide transporter DppBCDF, which is primed for glutathione transport by a dedicated periplasmic-binding protein (PBP). We have identified the periplasmic lipoprotein HbpA, a protein hitherto implicated in heme acquisition, as the cognate PBP that specifically binds reduced (GSH) and oxidized glutathione (GSSG) forms of glutathione with physiologically relevant affinity, while it exhibits marginal binding to hemin. Dissection of the ligand preferences of HbpA showed that HbpA does not recognize bulky glutathione S conjugates or glutathione derivatives with C-terminal modifications, consistent with the need for selective import of useful forms of glutathione and the concomitant exclusion of potentially toxic glutathione adducts. Structural studies of the highly homologous HbpA from Haemophilus parasuis in complex with GSSG have revealed the structural basis of the proposed novel function for HbpA-like proteins, thus allowing a delineation of highly conserved structure-sequence fingerprints for the entire family of HbpA proteins. Taken together, our studies unmask the main physiological role of HbpA and establish a paradigm for glutathione import in bacteria. Accordingly, we propose a name change for HbpA to glutathione-binding protein A.

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mentioning

confidence: 99%

Glutathione import in Haemophilus influenzae Rd is primed by the periplasmic heme-binding protein HbpA

Vergauwen

Elegheert

Dansercoer

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

104

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“…The regeneration of ascorbic acid from dehydroascorbic acid is not spontaneous. Reduction is mainly an enzymatically catalyzed reaction, which may be glutathione-dependent (Ishikawa et al 1998). Astrocytes are thought to be involved in ascorbic acid recycling (Figure 10, Astuya et al 2005).…”

Section: Metabolic Activation In Astrocytesmentioning

confidence: 99%

Brain Energy Metabolism in Health and Disease

Beltrán¹,

Acuña²,

Miró³

et al. 2012

Neuroscience - Dealing With Frontiers

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“…MRP1 is an ATP-binding cassette transporter that mediates the ATP-dependent export of glutathione conjugates out of cells [8]. Various kinds of agents clinically used for treatment have been reported to be able to block the transporter function of MRP1 [9].…”

Section: Introductionmentioning

confidence: 99%

Increased [18F]FMISO accumulation under hypoxia by multidrug-resistant protein 1 inhibitors

et al. 2021

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Background [18F]Fluoromisonidazole ([18F]FMISO) is a PET imaging probe widely used for the detection of hypoxia. We previously reported that [18F]FMISO is metabolized to the glutathione conjugate of the reduced form in hypoxic cells. In addition, we found that the [18F]FMISO uptake level varied depending on the cellular glutathione conjugation and excretion ability such as enzyme activity of glutathione-S-transferase and expression levels of multidrug resistance-associated protein 1 (MRP1, an efflux transporter), in addition to the cellular hypoxic state. In this study, we evaluated whether MRP1 activity affected [18F]FMISO PET imaging. Methods FaDu human pharyngeal squamous cell carcinoma cells were pretreated with MRP1 inhibitors (cyclosporine A, lapatinib, or MK-571) for 1 h, incubated with [18F]FMISO for 4 h under hypoxia, and their radioactivity was then measured. FaDu tumor-bearing mice were intravenously injected with [18F]FMISO, and PET/CT images were acquired at 4 h post-injection (1st PET scan). Two days later, the same mice were pretreated with MRP1 inhibitors (cyclosporine A, lapatinib, or MK-571) for 1 h, and PET/CT images were acquired (2nd PET scan). Results FaDu cells pretreated with MRP1 inhibitors exhibited significantly higher radioactivity than those without inhibitor treatment (cyclosporine A: 6.91 ± 0.27, lapatinib: 10.03 ± 0.47, MK-571: 10.15 ± 0.44%dose/mg protein, p < 0.01). In the in vivo PET study, the SUVmean ratio in tumors [calculated as after treatment (2nd PET scan)/before treatment of MRP1 inhibitors (1st PET scan)] of the mice treated with MRP1 inhibitors was significantly higher than those of control mice (cyclosporine A: 2.6 ± 0.7, lapatinib: 2.2 ± 0.7, MK-571: 2.2 ± 0.7, control: 1.2 ± 0.2, p < 0.05). Conclusion In this study, we revealed that MRP1 inhibitors increase [18F]FMISO accumulation in hypoxic cells. This suggests that [18F]FMISO-PET imaging is affected by MRP1 inhibitors independent of the hypoxic state.

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A new aspect on glutathione-associated biological function of MRP/GS-X pump and its gene expression

Cited by 3 publications

References 39 publications

Glutathione import in Haemophilus influenzae Rd is primed by the periplasmic heme-binding protein HbpA

Glutathione import in Haemophilus influenzae Rd is primed by the periplasmic heme-binding protein HbpA

Brain Energy Metabolism in Health and Disease

Increased [18F]FMISO accumulation under hypoxia by multidrug-resistant protein 1 inhibitors

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