Cytoprotective mechanisms of carbonyl scavenging drugs in isolated rat hepatocytes

Mehta, Rhea; Wong, Lawrence T.; O’Brien, Peter J.

doi:10.1016/j.cbi.2008.10.026

Cited by 39 publications

(25 citation statements)

References 55 publications

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“…2A). Concurring with observations made by Mehta et al (2009) using cultured cells, hydralazine displayed strong radical-quenching activity toward galvinoxyl radicals, exhibiting activity that matched or exceeded that of ascorbate or the vitamin E analog 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox; Hoffmann-La Roche, Nutley, NJ) ( Fig. 2A).…”

Section: Resultssupporting

confidence: 70%

“…Because the protective efficacy of hydralazine against chemically induced toxicity was suggested to involve antioxidant actions (Mehta et al, 2009), the galvinoxyl assay was used to compare the radical-trapping activity of hydralazine with that of established antioxidants ( Fig. 2A).…”

Section: Resultsmentioning

confidence: 99%

“…For example, in a hepatocyte model in which acrolein was generated enzymatically from allyl alcohol, hydralazine prevented cell death without lowering either extracellular "free acrolein" levels or the formation of protein adducts (Burcham et al, 2006). Others have also observed that hydralazine fails to block protein carbonylation in cultured cells, concluding instead that antioxidant actions mediate the cytoprotection (Mehta et al, 2009;Zheng and Bizzozero, 2010). …”

Section: Introductionmentioning

confidence: 99%

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Chaperone Heat Shock Protein 90 Mobilization and Hydralazine Cytoprotection against Acrolein-Induced Carbonyl Stress

Burcham

Raso²,

Kaminskas

2012

Mol Pharmacol

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Toxic carbonyls such as acrolein participate in many degenerative diseases. Although the nucleophilic vasodilatory drug hydralazine readily traps such species under "test-tube" conditions, whether these reactions adequately explain its efficacy in animal models of carbonyl-mediated disease is uncertain. We have previously shown that hydralazine attacks carbonyl-adducted proteins in an "adduct-trapping" reaction that appears to take precedence over direct "carbonyl-sequestering" reactions, but how this reaction conferred cytoprotection was unclear. This study explored the possibility that by increasing the bulkiness of acrolein-adducted proteins, adduct-trapping might alter the redistribution of chaperones to damaged cytoskeletal proteins that are known targets for acrolein. Using A549 lung adenocarcinoma cells, the levels of chaperones heat shock protein (Hsp) 40, Hsp70, Hsp90, and Hsp110 were measured in intermediate filament extracts prepared after a 3-h exposure to acrolein. Exposure to acrolein alone modestly increased the levels of all four chaperones. Coexposure to hydralazine (10 -100 M) strongly suppressed cell ATP loss while producing strong adduct-trapping in intermediate filaments. Most strikingly, hydralazine selectively boosted the levels of cytoskeletal-associated Hsp90, including a high-mass species that was sensitive to the Hsp90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin. Biochemical fractionation of acrolein-and hydralazine-treated cells revealed that hydralazine likely promoted Hsp90 migration from cytosol into other subcellular compartments. A role for Hsp90 mobilization in cytoprotection was confirmed by the finding that brief heat shock treatment suppressed acute acrolein toxicity in A549 cells. Taken together, these findings suggest that by increasing the steric bulk of carbonyl-adducted proteins, adduct-trapping drugs trigger the intracellular mobilization of the key molecular chaperone Hsp90.

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Section: Resultssupporting

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chaperone Heat Shock Protein 90 Mobilization and Hydralazine Cytoprotection against Acrolein-Induced Carbonyl Stress

Burcham

Raso²,

Kaminskas

2012

Mol Pharmacol

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“…LC 50 dose of the drug was determined and the protective effects of silafibrate and NAC against cell death induced by acetaminophen were tested. Hepatocytes were at least 85 % viable before their use, as recommended in previous studies (20)(21)(22)(23)(24)(25)(26)(27).…”

Section: Cell Viabilitymentioning

confidence: 99%

Cytoprotective effects of silafibrate, a newly-synthesised siliconated derivative of clofibrate, against acetaminophen-induced toxicity in isolated rat hepatocytes

Nafisi

Heidari²,

Ghaffarzadeh

et al. 2014

Archives of Industrial Hygiene and Toxicology

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Acetaminophen (N-acetyl para amino phenol, APAP) is a widely used antipyretic and analgesic drug responsible for various drug-induced liver injuries. This study evaluated APAP-induced toxicity in isolated rat hepatocytes alongside the protective effects of silafibrate and N-acetyl cysteine (NAC). Hepatocytes were isolated from male Sprague-Dawley rats by collagenase enzyme perfusion via the portal vein. This technique is based on liver perfusion with collagenase after removing calcium ions (Ca 2+) with a chelator. Cells were treated with different concentrations of APAP, silafibrate, and NAC. Cell death, reactive oxygen species (ROS) formation, lipid peroxidation, and mitochondrial depolarisation were measured as toxicity markers. ROS formation and lipid peroxidation occurred after APAP administration to rat hepatocytes. ) reduced the ROS formation, lipid peroxidation, and mitochondrial depolarisation caused by APAP. Cytotoxicity induced by APAP in rat hepatocytes was mediated by oxidative stress. In addition, APAP seemed to target cellular mitochondria during hepatocyte damage. The protective properties of silafibrate and/or NAC against APAP-induced hepatic injury may have involved the induction of antioxidant enzymes, protection against oxidative stress and inflammatory responses, and alteration in cellular glutathione content.

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“…Glyoxal toxicity has been thoroughly reviewed by Kielhorn et al (2004) and its toxicity, together with that of other dicarbonyls has been studied from long ago (Destaillats et al, 2002;Ueno et al, 1991). Glyoxal, methylglyoxal and glycolaldehyde produce adverse effects that promote cellular oxidation by attacking the antioxidative mechanisms of cells (Mehta, et al, 2009;Shangari et al, 2007;Al-Enezi et al, 2006;Shangari et al, 2003). Bifunctional carbonyls capacity to increase aerosol mass in the atmosphere through thermodynamical sorption processes as well as through heterogeneous reactions (Volkamer et al, 2007), increase their threat on human health since when they are absorbed in ultrafine particles can reach more easily the lungs.…”

Section: Introductionmentioning

confidence: 99%

Atmospheric Concentrations of Semivolatile Bifunctional Carbonyl Compounds and the Contribution from Motor Vehicles

Lobato-Ortíz¹,

Shimada²,

Sekiguchi³

et al. 2013

Asian J. Atmos. Environ

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Seven potentially harmful bifunctional carbonyls were measured in particulate and gaseous phases at a roadside site and a suburban site in an area about 30 km north-northwest from Tokyo metropolitan area in the Kanto region in Japan. For the first time, these compounds were measured in both phases with a time resolution of 2 h. We found that wind direction is an important parameter that affects the collection of these compounds near the source, and it can cover the effects of other important variables. Our results confirmed that motor vehicles and especially diesel fuelled vehicles are important sources of these compounds. Photochemical generation is also an important source of these compounds in the gaseous phase. Transportation from the urban area is also important, particularly in the aerosol phase.

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Cytoprotective mechanisms of carbonyl scavenging drugs in isolated rat hepatocytes

Cited by 39 publications

References 55 publications

Chaperone Heat Shock Protein 90 Mobilization and Hydralazine Cytoprotection against Acrolein-Induced Carbonyl Stress

Chaperone Heat Shock Protein 90 Mobilization and Hydralazine Cytoprotection against Acrolein-Induced Carbonyl Stress

Cytoprotective effects of silafibrate, a newly-synthesised siliconated derivative of clofibrate, against acetaminophen-induced toxicity in isolated rat hepatocytes

Atmospheric Concentrations of Semivolatile Bifunctional Carbonyl Compounds and the Contribution from Motor Vehicles

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