Target identification of drug induced mitochondrial toxicity using immunocapture based OXPHOS activity assays

Nadanaciva, Sashi; Bernal, Autumn J.; Aggeler, Robert; Capaldi, Roderick A.; Will, Yvonne

doi:10.1016/j.tiv.2007.01.011

Cited by 117 publications

(81 citation statements)

References 26 publications

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“…This was accompanied by a decrease in cell mass to 0.22 times for 48 h, and 0.14 times for 72 h, when compared to DMSO, being always lower when compared to the same conditions in cells cultured in glucose-containing medium. These results are in accordance with previous reports (Dykens et al, 2008;Nadanaciva et al, 2007) and are suggestive of mitochondrial involvement in NEF hepatotoxicity. These alterations were accompanied by early gene expression changes.…”

Section: Discussionsupporting

confidence: 94%

“…NEF hepatotoxicity was previously reported to be associated with mitochondrial impairment, due to interference with OXPHOS enzymatic activities (Dykens et al, 2008;Nadanaciva et al, 2007), increased ROS generation and decreased antioxidant defenses (Dykens et al, 2008). However, the mechanisms underlying NEFinduced mitochondrial dysfunction in hepatocytes are not completely understood.…”

Section: Discussionmentioning

confidence: 99%

“…The same work showed that NEF treatment resulted in inhibition of both bile acid transport, via the bile salt export pump (BSEP) present in membrane vesicles, and the canalicular transport in cultured human hepatocytes (Kostrubsky et al, 2006). NEF was also shown to directly impair hepatic mitochondrial function through inhibition of OXPHOS complexes, particularly complex I (Dykens et al, 2008;Nadanaciva et al, 2007). Although mitochondrial dysfunction seems to be a major player behind NEF hepatotoxicity, there are only a few reports describing the possible mechanisms involved (Dykens et al, 2008;Kim et al, 2012;Swiss et al, 2013;Xu et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Involvement of mitochondrial dysfunction in nefazodone-induced hepatotoxicity

Silva

Barbosa

Seabra

et al. 2016

Food and Chemical Toxicology

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a b s t r a c tNefazodone (NEF) is an antidepressive agent that was widely used in the treatment of depression until its withdrawal from the market, due to reports of liver injury and failure. NEF hepatotoxicity has been associated with mitochondrial impairment due to interference with the OXPHOS enzymatic activities, increased ROS generation and decreased antioxidant defenses. However, the mechanisms by which NEF induces mitochondrial dysfunction in hepatocytes are not completely understood. Here, we investigated the mitochondrial mechanisms affected upon NEF exposure and whether these might be linked to drug hepatotoxicity, in order to infer liabilities of future drug candidates.Two moderately hepatotoxic NEF concentrations (20 and 50 mM) were selected from dose-response growth curves performed in HepG2 cells. Cell viability, caspase activity, nuclear morphology, mitochondrial transmembrane potential, mitochondrial superoxide levels, and the expression of genes associated with different cellular pathways were evaluated at different time points.NEF treatment led to an increase in the expression of genes associated with DNA-damage response, antioxidant defense and apoptosis and a decreased expression of genes encoding proteins involved in oxidative phosphorylation, DNA repair, cell proliferation and cell cycle progression, which seem to constitute mechanisms underlying the observed mitochondrial and cell function impairment.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Involvement of mitochondrial dysfunction in nefazodone-induced hepatotoxicity

Silva

Barbosa

Seabra

et al. 2016

Food and Chemical Toxicology

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“…Tamoxifen, developed as an estrogen receptor (ER) antagonist, is also an ATP synthase inhibitor without obvious chemical reactivity; and both tamoxifen and amiodarone inhibit additional points in the electron transport chain, even though the proteins inhibited are disparate in chemical structure. [71] These results together imply a role for membrane disruption by highly hydrophobic compounds in cytotoxicity, and oxidative phosphorylation appears to be sensitive to this type of inhibition.…”

Section: Promiscuous Compoundsmentioning

confidence: 94%

“…[69,70] They are also relatively potent inhibitors of ATP synthase, which is a membrane-bound protein. [71] While reactive metabolites are produced by chlorpromazine, amiodarone is not an obvious source of chemical reactivity. Tamoxifen, developed as an estrogen receptor (ER) antagonist, is also an ATP synthase inhibitor without obvious chemical reactivity; and both tamoxifen and amiodarone inhibit additional points in the electron transport chain, even though the proteins inhibited are disparate in chemical structure.…”

Section: Promiscuous Compoundsmentioning

confidence: 99%

The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing

Kohonen

Benfenati

Bower

et al. 2013

Molecular Informatics

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The aim of the SEURAT‐1 (Safety Evaluation Ultimately Replacing Animal Testing‐1) research cluster, comprised of seven EU FP7 Health projects co‐financed by Cosmetics Europe, is to generate a proof‐of‐concept to show how the latest technologies, systems toxicology and toxicogenomics can be combined to deliver a test replacement for repeated dose systemic toxicity testing on animals. The SEURAT‐1 strategy is to adopt a mode‐of‐action framework to describe repeated dose toxicity, combining in vitro and in silico methods to derive predictions of in vivo toxicity responses. ToxBank is the cross‐cluster infrastructure project whose activities include the development of a data warehouse to provide a web‐accessible shared repository of research data and protocols, a physical compounds repository, reference or “gold compounds” for use across the cluster (available via wiki.toxbank.net), and a reference resource for biomaterials. Core technologies used in the data warehouse include the ISA‐Tab universal data exchange format, REpresentational State Transfer (REST) web services, the W3C Resource Description Framework (RDF) and the OpenTox standards. We describe the design of the data warehouse based on cluster requirements, the implementation based on open standards, and finally the underlying concepts and initial results of a data analysis utilizing public data related to the gold compounds.

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OXPHOS Complex Activity Assays and Dipstick Immunoassays for Assessment of OXPHOS Protein Levels

Nadanaciva¹

2008

Drug‐Induced Mitochondrial Dysfunction

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Target identification of drug induced mitochondrial toxicity using immunocapture based OXPHOS activity assays

Cited by 117 publications

References 26 publications

Involvement of mitochondrial dysfunction in nefazodone-induced hepatotoxicity

Involvement of mitochondrial dysfunction in nefazodone-induced hepatotoxicity

The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing

OXPHOS Complex Activity Assays and Dipstick Immunoassays for Assessment of OXPHOS Protein Levels

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