Biomarkers of in Vitro Drug‐Induced Mitochondrial Dysfunction

Dykens, James A.; Will, Yvonne

doi:10.1002/9780470918562.ch16

Cited by 22 publications

(42 citation statements)

References 73 publications

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“…Over the past decade, interest in screening chemicals for an ability to induce mitochondrial dysfunction has increased. 24,25 This is, in part, due to the withdrawal of a number of pharmaceuticals from the market after observed mitochondrial dysfunctions. [26][27][28][29][30][31] Toxicity to mitochondria has led to such withdrawals as these are important organelles present within almost every cell type of the body, the exception being mature erythrocytes.…”

Section: -12mentioning

confidence: 99%

“…25,31,34 Complex V, the terminal complex involved in oxidative phosphorylation, utilises the electrochemical gradient produced to transfer protons from the inter membrane space back into the mitochondrial matrix. The energy released from this action is used to phosphorylate adenosine diphosphate into ATP.…”

Section: -12mentioning

confidence: 99%

“…[26][27][28][29][30][31]35 The most susceptible tissues to mitochondrial dysfunction are those containing a higher concentration of mitochondria or those exposed to a higher concentration of chemical: such as the liver, kidneys and heart. 24,25,28,36 Given the importance of mitochondria within most cell systems, and the wide range of organ-level toxicities that may arise from mitochondrial dysfunction, the aim of the study was to identify structural alerts that could be used to form an in silico profiler suitable for grouping chemicals into mechanism-based categories. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 8…”

Section: -12mentioning

confidence: 99%

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Development of an in Silico Profiler for Mitochondrial Toxicity

Nelms

Mellor

Cronin

et al. 2015

Chem. Res. Toxicol.

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This study outlines the analysis of mitochondrial toxicity for a variety of pharmaceutical drugs extracted from Zhang et al. These chemicals were grouped into categories based upon structural similarity. Subsequently, mechanistic analysis was undertaken for each category to identify the Molecular Initiating Event driving mitochondrial toxicity. The mechanistic information elucidated during the analysis enabled mechanism-based structural alerts to be developed and combined together to form an in silico profiler. This profiler is envisaged to be used to develop chemical categories based upon similar mechanisms as part of the Adverse Outcome Pathway paradigm. Additionally, the profiler could be utilised in screening large dataset in order to identify chemicals with the potential to induce mitochondrial toxicity.

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Section: -12mentioning

confidence: 99%

Section: -12mentioning

confidence: 99%

Section: -12mentioning

confidence: 99%

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Development of an in Silico Profiler for Mitochondrial Toxicity

Nelms

Mellor

Cronin

et al. 2015

Chem. Res. Toxicol.

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“…Many xenobiotics are capable of inducing mitochondrial injury. Among these, several pharmaceuticals are reported to affect mitochondrial function [11,12]. Energy metabolism disorders can affect practically any organ.…”

Section: Introductionmentioning

confidence: 99%

Sulfasalazine induces mitochondrial dysfunction and renal injury

et al. 2017

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Sulfasalazine is a commonly used drug for the treatment of rheumatoid arthritis and inflammatory bowel disease. There are several cases of renal injury encompass sulfasalazine administration in humans. The mechanism of sulfasalazine adverse effects toward kidneys is obscure. Oxidative stress and its consequences seem to play a role in the sulfasalazine-induced renal injury. The current investigation was designed to investigate the effect of sulfasalazine on kidney mitochondria. Rats received sulfasalazine (400 and 600 mg/kg/day, oral) for 14 consecutive days. Afterward, kidney mitochondria were isolated and assessed. Sulfasalazine-induced renal injury was biochemically evident by the increase in serum blood urea nitrogen (BUN), gamma-glutamyl transferase (c-GT), and creatinine (Cr). Histopathological presentations of the kidney in sulfasalazine-treated animals revealed by interstitial inflammation, tubular atrophy, and tissue necrosis. Markers of oxidative stress including an increase in reactive oxygen species (ROS) and lipid peroxidation (LPO), a defect in tissue antioxidant capacity, and glutathione (GSH) depletion were also detected in the kidney of sulfasalazine-treated groups. Decreased mitochondrial succinate dehydrogenase activity (SDA), mitochondrial depolarization, mitochondrial GSH depletion, increase in mitochondrial ROS, LPO, and mitochondrial swelling were also evident in sulfasalazine-treated groups. Current data suggested that oxidative stress and mitochondrial injury might be involved in the mechanism of sulfasalazine-induced renal injury. ARTICLE HISTORY

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“…37 Approximately onethird of over 500 pharmaceuticals inhibit mitochondrial respiration or impair electron transport. 46 Mitochondrial dysfunction can be caused by a diverse array of drugs, including antibiotics, antiretrovirals, antidepressants, antianginals, nonsteroidal anti-inflammatory agents, anticonvulsants, anesthetics, antiarrhythmics, and oncology agents. 37,47 In drugs initiating mitochondrial dysfunction, liver injury develops gradually over weeks, because cumulative mitochondrial impairment reaches a critical threshold with clinically evident liver injury (apoptosis or necrosis).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-induced liver injury: A systematic review

Hunt

2010

Hepatology

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Biomarkers of in Vitro Drug‐Induced Mitochondrial Dysfunction

Cited by 22 publications

References 73 publications

Development of an in Silico Profiler for Mitochondrial Toxicity

Development of an in Silico Profiler for Mitochondrial Toxicity

Sulfasalazine induces mitochondrial dysfunction and renal injury

Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-induced liver injury: A systematic review

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