Transport of ebselen in plasma and its transfer to binding sites in the hepatocyte

Wagner, G; Schuch, Gunter; Akerboom, Theodorus P.M.; Sies, Helmut

doi:10.1016/0006-2952(94)90150-3

Cited by 53 publications

(31 citation statements)

References 21 publications

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“…Covalent Binding of MitoPeroxidase to Mitochondrial Thiol Proteins-The isoselenazole moiety may lead to MitoPeroxidase binding to mitochondria through reaction with mitochondrial thiols, as ebselen is known to form selenenylsulfide bonds with protein thiols, glutathione, and cysteine (9,35,36,66,67). To determine whether MitoPeroxidase formed selenenylsulfide bonds with mitochondrial protein thiols, we incubated MitoPeroxidase with bovine heart mitochondrial membranes.…”

Section: Resultsmentioning

confidence: 99%

“…Although ebselen has been used to a limited extent in mitochondrial studies, both toxic and protective effects have been reported, and it is unclear if ebselen is activated by mitochondrial GSH and Trx (32)(33)(34). In addition, there are indications that ebselen may bind covalently to proteins in vivo, but the nature and extent of this putative binding is unclear (35,36). A peroxidase mimetic that was accumulated selectively by mitochondria would be of interest.…”

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confidence: 99%

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Synthesis and Characterization of a Triphenylphosphonium-conjugated Peroxidase Mimetic

Filipovska

Kelso

Brown

et al. 2005

Journal of Biological Chemistry

128

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Mitochondrial production of peroxides is a critical event in both pathology and redox signaling. Consequently their selective degradation within mitochondria is of considerable interest. Here we have explored the interaction of the peroxidase mimetic ebselen with mitochondria. We were particularly interested in whether ebselen was activated by mitochondrial glutathione (GSH) and thioredoxin, in determining whether an ebselen moiety could be targeted to mitochondria by conjugating it to a lipophilic cation, and in exploring the nature of ebselen binding to mitochondrial proteins. To achieve these goals we synthesized 2-[4-(4-triphenylphosphoniobutoxy) phenyl]-1,2-benzisoselenazol)-3(2H)-one iodide (MitoPeroxidase), which contains an ebselen moiety covalently linked to a triphenylphosphonium (TPP) cation. The fixed positive charge of TPP facilitated mass spectrometric analysis, which showed that the ebselen moiety was reduced by GSH to the selenol form and that subsequent reaction with a peroxide reformed the ebselen moiety. MitoPeroxidase and ebselen were effective antioxidants that degraded phospholipid hydroperoxides, prevented lipid peroxidation, and protected mitochondria from oxidative damage. Both peroxidase mimetics required activation by mitochondrial GSH or thioredoxin to be effective antioxidants. Surprisingly, conjugation to the TPP cation led to only a slight increase in the uptake of ebselen by mitochondria due to covalent binding of the ebselen moiety to proteins. Using antiserum against the TPP moiety we visualized those proteins covalently attached to the ebselen moiety. This analysis indicated that much of the ebselen present within mitochondria is bound to protein thiols through reversible selenenylsulfide bonds. Both MitoPeroxidase and ebselen decreased apoptosis induced by oxidative stress, suggesting that they can decrease mitochondrial oxidative stress. This exploration has led to new insights into the behavior of peroxidase mimetics within mitochondria and to their use in investigating mitochondrial oxidative damage.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Synthesis and Characterization of a Triphenylphosphonium-conjugated Peroxidase Mimetic

Filipovska

Kelso

Brown

et al. 2005

Journal of Biological Chemistry

128

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“…In previous researches, it was demonstrated that ebselen could covalently bound to plasma protein by selenium-sulfur bond [7,8], and glutathione can catalyze an exchange of this covalently bound ebselen forming the selenosulfide adduct [9,10]. The process contributed to the equilibrium between plasma and target protein [9].…”

Section: Introductionmentioning

confidence: 99%

High performance liquid chromatographic determination of 1,2-[bis(1,2-benzisoselenazolone-3(2H)-ketone)]-ethane (BBSKE), a novel organoselenium compound, in dog plasma using pre-column derivatization and its application in pharmacokinetic study

Zhou¹,

Dou²,

Zhang³

et al. 2007

Journal of Chromatography B

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“…For one, EB-1 binds strongly to plasma proteins when administered intravenously and can not reach the cell in the albumin-bound state. It takes thiol-containing reducing agents to free EB-1 to bind to membraneassociated proteins (33). Moreover, the antiinfl ammatory activity of EB-1 is not likely to be involved in the protection against mustard toxicity observed in this study because like other in vitro models, A-431 skin cells do not possess a vasculature, connective tissue, or immune cells.…”

Section: Discussionmentioning

confidence: 87%

Ebselen Analogues Reduce 2-chloroethyl Ethyl Sulphide Toxicity in A-431 Cells

Pino

Pįętka-Ottlik

Billack

2013

Archives of Industrial Hygiene and Toxicology

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Vesicants are potent blistering agents. The prototype vesicant is sulphur mustard gas, fi rst used in World War I, which still has no effective antidote. We used a mustard gas surrogate 2-chloroethyl ethyl sulphide (CEES) to study the ability of resveratrol (RES) and pterostilbene (PTS), two well-established stilbene antioxidants, ebselen (EB-1), an organoselenium compound, and three EB-1 analogues (EB-2, EB-3, and EB-4) to reduce CEES toxicity in human epidermoid carcinoma cells (A-431). Following a 24-hour incubation of a toxic concentration of CEES (1000 μmol L ) did not decrease cell viability. Treatment with CEES and test antioxidants for 24 h showed that only EB-1 and its analogues EB-2, EB-3, and EB-4 but not the stilbene compounds could rescue the cells from death. EB-1 and EB-4 were the most effective at reducing CEES cytotoxicity and did so in a concentration-dependent manner, while EB-2 and EB-3 demonstrated the least protective effect. In summary, the data described herein indicate that organoselenium antioxidants, especially EB-4, may prove useful as countermeasures to blistering agents.

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Transport of ebselen in plasma and its transfer to binding sites in the hepatocyte

Cited by 53 publications

References 21 publications

Synthesis and Characterization of a Triphenylphosphonium-conjugated Peroxidase Mimetic

Synthesis and Characterization of a Triphenylphosphonium-conjugated Peroxidase Mimetic

High performance liquid chromatographic determination of 1,2-[bis(1,2-benzisoselenazolone-3(2H)-ketone)]-ethane (BBSKE), a novel organoselenium compound, in dog plasma using pre-column derivatization and its application in pharmacokinetic study

Ebselen Analogues Reduce 2-chloroethyl Ethyl Sulphide Toxicity in A-431 Cells

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