Inhibition of glutathione-related enzymes and cytotoxicity of ethacrynic acid and cyclosporine

Hoffman, Denise; Wiebkin, Philip; Rybak, Leonard P.

doi:10.1016/0006-2952(94)00474-z

Cited by 19 publications

(10 citation statements)

References 32 publications

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“…Potentiation of cisplatin nephrotoxicity has been reported with GSH depletion (Nakano & Gemba 1989;Kameyama & Gemba 1991;Ishikawa et al 1990). Hoffman et al 1995 reported a role for GSH-mediated detoxification mechanisms in ethacrynic acid-and cyclosporin-associated cytotoxicity that may mediate their toxicities and their potential as adjunctive agents in antineoplastic therapy. A better understanding of the mechanisms of toxicity of cisor transplatin buthionine sulfoximine, loop diuretics cyclosporine A and aminoglycoside can greatly extend the clinical usefulness of these agents, as this toxicity (depletion of glutathione reductase and glutathione-S-transferase) is the basis of both their therapeutic and antitherapeutic action.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Cisplatin Ototoxicity: Antioxidant System

Ravi¹,

Somani²,

Rybak

1995

Pharmacology & Toxicology

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295

194

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The dose and duration limiting toxic effects of cisplatin are ototoxicity and nephrotoxicity. While several studies have attempted to shed some light on the causes of nephrotoxicity, the reasons for ototoxicity induced by cisplatin are poorly understood. Therefore, this investigation was undertaken to delineate the potential mechanisms underlying cisplatin ototoxicity. The role of glutathione (GSH), oxidized glutathione (GSSG) and malondialdehyde levels, and antioxidant enzyme activities [superoxide dismutase, catalase, GSH peroxidase, and GSH reductase] were examined in cochlear toxicity following an acute dose of cisplatin. Male Wistar rats were treated with various doses of cisplatin. Pretreatment auditory brain stem evoked responses (ABR) were performed and then post-treatment ABRs and endocochlear potentials were also performed after three days. Acute cochlear toxicity (ototoxicity) was evidenced as elevated hearing thresholds and prolonged wave I latencies in response to various stimuli (clicks and tone bursts at 2, 8, 16 and 32 kHz) on ABRs. The endocochlear potentials were reduced (50% control) in cisplatin-treated rats as compared to control animals. The rats were sacrificed and cochleae isolated. The GSH, GSSG and malondialdehyde levels, and antioxidant enzyme activities were determined. Cisplatin ototoxicity correlated with a decrease in cochlear GSH [0.45 +/- 0.012 nmol/mg] after cisplatin administration compared to 0.95-012 nmol/mg in control cochleae (P < 0.05). Superoxide dismutase, catalase activities and malondialdehyde levels were significantly increased in the cochleae of cisplatin injected rats. Cochlear GSH-peroxidase and GSH reductase activity significantly decreased after cisplatin administration.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 99%

Mechanism of Cisplatin Ototoxicity: Antioxidant System

Ravi¹,

Somani²,

Rybak

1995

Pharmacology & Toxicology

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295

194

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“…Ethacrynic acid inhibited glutathione-S-transferase by irreversibly binding to the enzyme (Yamada & Kaplowitz 1980;Ahokas et al 1985;Ploeman et al 1990Ploeman et al & 1993Awasthi et al 1993). It also inhibited glutathione reductase (Hoffman et al 1995). These reports suggest that lipid peroxidation may play an important role in the ethacrynic acid-induced hepatotoxicity.…”

mentioning

confidence: 81%

Rat Liver Microsomal Lipid Peroxidation Produced during the Oxidative Metabolism of Ethacrynic Acid

Yamamoto

Masubuchi

Narimatsu

et al. 2001

Pharmacology & Toxicology

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Thiobarbituric acid reactive substances (TBARS) were produced in rat liver microsomal suspension incubated with ethacrynic acid (loop diuretic drug) and NADPH. Two oxidative metabolites of ethacrynic acid with dicarboxylic acid and hydroxylated ethyl group, respectively, were formed in the reaction mixture. The oxidative metabolism of ethacrynic acid was inhibited by cytochrome P450 inhibitors. The formation of TBARS was remarkably depressed by inhibitors like diethyldithiocarbamate and disulfiram. These results indicate that lipid peroxidation occurred in rat liver microsomes through the oxidative metabolism of ethacrynic acid.

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“…This may be connected to the conditions used for the assays: these open questions concern i) binding to the active site or an allosteric binding site, ii) the reversibility or irreversibility of inhibition, iii) the type of inhibition (competitive or uncompetitive toward various substrates), and iv) the inhibitory potency of ethacrynic acid in comparison to the poteny of its GSH conjugates. The drug also inhibits other enzymes, such as glutathione reductase [181], asparagine synthetase [182], and even angiotensin converting enzyme (ACE) [183].…”

Section: Inhibitors Containing An Activated Double Bond: Methylene Kementioning

confidence: 99%

Inhibitors of Cysteine Proteases

Vičík¹,

Busemann²,

Baumann³

et al. 2006

CTMC

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The roles of cysteine proteases (CP) as protein degrading and protein processing enzymes both in physiological and pathological processes of mammals are well known. Furthermore, the key roles of CP;s in the life cycles of infectious agents like protozoa and viruses turn them into new important targets for anti-infective drugs. Thus, the effective inhibition of pathologically relevant cysteine proteases has raised increasing interest in drug development. One strategy to create CP inhibitors is the use of electrophilic moieties, which covalently bind to the cysteine residue of the active site of the target protease. In a previous approach we have selected the aziridine-2,3-dicarboxylic acid as weak electrophilic inhibitor fragment. In order to achieve effective enzyme inhibition this electrophile was incorporated into peptidic or peptidomimetic sequences addressing the substrate binding sites of the protease. High selectivity could be obtained with compounds, which bind into both the primed and non-primed substrate binding pockets. In a second approach the alpha,beta-unsaturated ketone of the well-known diuretic drug ethacrynic acid was found to be another appropriate electrophilic moiety. Derivatives thereof turned out to be new non-peptidic CP inhibitors. Results of inhibition assays obtained with these two inhibitor series on various proteases of human, protozoan, and viral origin, theoretical studies to investigate binding modes and inhibition mechanisms, and structure-activity relationships are presented. Furthermore, the results of in vitro assays on respective pathogens as well as the results of first toxicity studies are summarized.

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Inhibition of glutathione-related enzymes and cytotoxicity of ethacrynic acid and cyclosporine

Cited by 19 publications

References 32 publications

Mechanism of Cisplatin Ototoxicity: Antioxidant System

Mechanism of Cisplatin Ototoxicity: Antioxidant System

Rat Liver Microsomal Lipid Peroxidation Produced during the Oxidative Metabolism of Ethacrynic Acid

Inhibitors of Cysteine Proteases

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