Glutathione as a scavenger of free hemin

Shviro, Yocheved; Shaklai, Nurith

doi:10.1016/0006-2952(87)90441-2

Cited by 61 publications

(18 citation statements)

References 17 publications

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“…Erythrocyte suspensions (0.6 ml) were shaken with various concentrations of heme (0 -20 M) and CLT or CQ (0, 1, 5, and 10 M) at 37°C for 150 min at 140 cycles/min. Intact erythrocytes were then removed by centrifugation at 1,500 ϫ g for 3 min, and the amount of hemoglobin released from the hemolyzed erythrocytes into the supernatant was determined by measuring absorbance at 578 nm (26). After the pelleted intact erythrocytes were lysed with water and centrifuged to obtain the supernatant, the hemoglobin content in intact erythrocytes was measured as absorbance at 578 nm.…”

Section: Gsh-dependent Heme Degradation and Its Inhibition By Clt Ormentioning

confidence: 99%

“…After the pelleted intact erythrocytes were lysed with water and centrifuged to obtain the supernatant, the hemoglobin content in intact erythrocytes was measured as absorbance at 578 nm. The degree of hemolysis was calculated from the ratio of hemoglobin content released from erythrocytes hemolyzed by heme to the total heme content of the erythrocytes (26).…”

Section: Gsh-dependent Heme Degradation and Its Inhibition By Clt Ormentioning

confidence: 99%

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Clotrimazole Binds to Heme and Enhances Heme-dependent Hemolysis

Huy

Kamei

Yamamoto

et al. 2002

Journal of Biological Chemistry

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Two recent studies have demonstrated that clotrimazole, a potent antifungal agent, inhibits the growth of chloroquine-resistant strains of the malaria parasite, Plasmodium falciparum, in vitro. We explored the mechanism of antimalarial activity of clotrimazole in relation to hemoglobin catabolism in the malaria parasite. Because free heme produced from hemoglobin catabolism is highly toxic to the malaria parasite, the parasite protects itself by polymerizing heme into insoluble nontoxic hemozoin or by decomposing heme coupled to reduced glutathione. We have shown that clotrimazole has a high binding affinity for heme in aqueous 40% dimethyl sulfoxide solution (association equilibrium constant: K a ‫؍‬ 6.54 ؋ 10 8 M ؊2 ). Even in water, clotrimazole formed a stable and soluble complex with heme and suppressed its aggregation. The results of optical absorption spectroscopy and electron spin resonance spectroscopy revealed that the heme-clotrimazole complex assumes a ferric low spin state (S ‫؍‬ 1 ⁄2), having two nitrogenous ligands derived from the imidazole moieties of two clotrimazole molecules. Furthermore, we found that the formation of heme-clotrimazole complexes protects heme from degradation by reduced glutathione, and the complex damages the cell membrane more than free heme. The results described herein indicate that the antimalarial activity of clotrimazole might be due to a disturbance of hemoglobin catabolism in the malaria parasite.

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Section: Gsh-dependent Heme Degradation and Its Inhibition By Clt Ormentioning

confidence: 99%

Section: Gsh-dependent Heme Degradation and Its Inhibition By Clt Ormentioning

confidence: 99%

Clotrimazole Binds to Heme and Enhances Heme-dependent Hemolysis

Huy

Kamei

Yamamoto

et al. 2002

Journal of Biological Chemistry

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“…18) Briefly, the erythrocyte suspension was centrifuged at 1500ϫg for 3 min to collect non-hemolyzed erythrocytes, and the amount of hemoglobin in the supernatant was determined by absorbance at 578 nm. 24) The hemoglobin content in the sedimented non-hemolyzed erythrocytes was measured following lysis in distilled water. The percent hemolysis was calculated from the ratio of hemoglobin content of hemolyzed erythrocytes to that of the total erythrocytes.…”

Section: Lipid Peroxidation By Heme and Heme-clt Complexmentioning

confidence: 99%

Enhancement of Heme-Induced Membrane Damage by the Anti-malarial Clotrimazole: the Role of Colloid-Osmotic Forces

Huy

Takano

Hara

et al. 2004

Biological & Pharmaceutical Bulletin

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“…Indeed, Sahini and coworkers demonstrated that GSH prevents erythrocyte damage by hemin. In an earlier publication, Shviro and Shaklai [9] also demonstrated that GSH is a scavenger of free hemin and calculated that at least 97% of cytosolic hemin is complexed with glutathione. These data led to their proposal that GSH may serve physiologically as the cytosolic chelator of free hemin [9].…”

Section: University Of Missourimentioning

confidence: 99%

“…In an earlier publication, Shviro and Shaklai [9] also demonstrated that GSH is a scavenger of free hemin and calculated that at least 97% of cytosolic hemin is complexed with glutathione. These data led to their proposal that GSH may serve physiologically as the cytosolic chelator of free hemin [9]. We have spectroscopic evidence for the formation of a GSH/heme conjugate when hemin is treated with dithionite in the presence of excess GSH.…”

Section: University Of Missourimentioning

confidence: 99%

2015 BioIron Meeting Abstracts

2016

American J Hematol

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BackgroundIron is central to the aetiology of gastrointestinal disease. Specifically, the toxic effects of excess, unabsorbed 'luminal' iron ingested from the diet has been shown to be important in the development of inflammatory bowel disease and intestinal carcinogenesis. A platform for therapeutic intervention is likely to involve chelation of this 'luminal' pool of iron specifically without interfering with systemic iron. Therefore, a range of iron-chelating polymers, known as alginates, have been tested for their iron binding capacity. Alginates are natural, non-absorbable and non-fermentable bio-polymers which can therefore be employed to bind residual dietary colonic iron without becoming absorbed during gastro-intestinal transit. Materials methodsThe structural and physicochemical properties of alginate-iron binding were assessed using high resolution scanning transmission electron spectroscopy (STEM) and circular dichroism spectroscopy. Cell lines were stimulated with iron in the presence and absence of sodium alginates (ManDH, ManLD, LFR, RF, GHB, PROT and KEL at 0.3% w/v) and effects on cellular iron levels were assessed using the radioactive ( 59 Fe) uptake assays and ferritin analysis. CACOII models of intestinal absorption were performed to examine the dynamics of iron trafficking through the cell monolayer when treated with alginates. Furthermore, In vivo studies were performed to 1) assess the potential of alginate solutions (8% w/v) to bind iron within the gastrointestinal tract by utilising radioactive iron and to 2) assess its potential anti-cancer activity. Results A range of alginates were utilised and their iron binding potential was assessed. The chemical interaction between alginate and iron was studied using STEM, which revealed alginate-supported iron oxide nanoparticle formation. In vitro studies confirmed that alginate mediated cellular iron chelation as exemplified by decreased cellular iron levels and ferritin expression. The effect was most profound for one alginate, namely ManLD. Ferritin expression reduced by 60% (p = 0.03) in cells challenged with ManLD and iron compared to cells challenged with iron alone. Cellular iron also decreased by 70% (p=0.001) when treated similarly. Furthermore, ManLD was shown to decrease intestinal iron absorption by 83% (p= 0.002) compared to an iron only control and was also able to suppress tumorigenesis in a murine intestinal cancer model, increasing median survival by 26 days (p = 0.007) compared to mice treated with vehicle alone. Conclusions Sodium alginate is an excellent candidate for sequestering luminal iron present in the gastrointestinal tract and in vivo shows promising anti-neoplastic activity. These results underpin the rationale in utilising these types of natural and safe bio-polymers for the prevention and treatment of gastrointestinal disease. E21 Poster #2 NOVEL 3-HYDROXYPYRIDIN-4-ONE HEXADENTATE LIGAND-BASED POLYMERIC IRON CHELATOR: SYNTHESIS, CHARACTERIZATION AND ANTIMICROBIAL EVALUATIONTao Zhou, Yingjun Zhou, MSc, Xiaole Kong,...

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Glutathione as a scavenger of free hemin

Cited by 61 publications

References 17 publications

Clotrimazole Binds to Heme and Enhances Heme-dependent Hemolysis

Clotrimazole Binds to Heme and Enhances Heme-dependent Hemolysis

Enhancement of Heme-Induced Membrane Damage by the Anti-malarial Clotrimazole: the Role of Colloid-Osmotic Forces

2015 BioIron Meeting Abstracts

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