Troglitazone, but not rosiglitazone, damages mitochondrial DNA and induces mitochondrial dysfunction and cell death in human hepatocytes

Rachek, Lyudmila I.; Yuzefovych, Larysa V.; LeDoux, Susan P.; Julie, Neil L.; Wilson, Glenn L.

doi:10.1016/j.taap.2009.07.021

Cited by 88 publications

(53 citation statements)

References 36 publications

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“…Cyclosporine A is known to inhibit opening of the mitochondrial permeability transition pore (Crompton et al, 1988), thereby protecting cells against mitochondrial dysfunction and death. On the other hand, fialuridine and troglitazone are reported to induce mitochondrial dysfunction (Tujios and Fontana, 2011;Rachek et al, 2009). In particular, fialuridine decreases the number of mitochondrial cristae (McKenzie et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Utility of human hepatocyte spheroids for evaluation of hepatotoxicity

Ogihara

Iwai

Inoue³

et al. 2015

Fundam. Toxicol. Sci.

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-Drug-induced hepatotoxicity is a common reason for discontinuing the development of candidate clinical drugs. In the present study, we investigated the utility of three-dimensionally cultured human hepatocytes (spheroids) for prediction of hepatotoxicity, using a panel of model drugs: acetaminophen, benzbromarone, chlorpromazine, cyclosporin A, diclofenac, fialuridine, flutamide, imipramine, isoniazid, ticlopidine and troglitazone. Cultured spheroids showed a significant increase of albumin secretion from 2 to 7 days; the secretion started to decrease at 14 days, but continued from 14 days to 21 days. The morphology of the spheroids was well maintained for 21 days. Long-term exposure of spheroids to hepatotoxic drugs resulted in concentration-dependent depression of albumin secretion and elevation of aspartate aminotransferase (AST) leakage. The estimated 50% effective concentration (IC 50 ) values for decrease of albumin secretion changed from 7 days to 14 days, but similar values were obtained at 14 and 21 days, except for diclofenac. Since the IC 50 values and the values of drug concentration inducing 1.2-fold elevation of AST leakage (F1.2) were similar at 14 and 21 days, an incubation period of 14 days was

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Section: Discussionmentioning

confidence: 99%

Utility of human hepatocyte spheroids for evaluation of hepatotoxicity

Ogihara

Iwai

Inoue³

et al. 2015

Fundam. Toxicol. Sci.

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“…For instance APAP and troglitazone can induce mtDNA strand breaks which eventually lead to a reduction of mtDNA levels [141,142]. Indeed, damaged mtDNA molecules harboring numerous strand breaks can be rapidly degraded by mitochondrial endonucleases [143][144][145].…”

Section: Drug-induced Severe Inhibition Of Mitochondrial B-oxidation mentioning

confidence: 99%

Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver

Begriche¹,

Massart²,

Robin³

et al. 2011

Journal of Hepatology

457

413

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Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis).

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“…48 The mechanism of hepatotoxicity could be ascribed to mitochondrial DNA damage caused by this drug. 49 …”

Section: Troglitazonementioning

confidence: 99%

Drugs acting on mitochondrial pathways

Srinivasan

Selvarajan

Dkhar

et al. 2017

Int J Basic Clin Pharmacol

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Mitochondrion, “the power house” of the cell plays a vital role in generating energy for the intricate functions of the cells. Mitochondria also play important roles in various apoptotic pathways. Around 80-90% of the ATP generated in cells is contributed by these organelles through the process of oxidative phosphorylation. Though this process is essential for the functioning of cells it also generates various Reactive Oxygen Species (ROS), which are toxic to cells. Hence mitochondrial dysfunction is hypothesized to be an important factor in the occurrence of disorders related to aging such as neurodegeneration and malignancies. Several commonly used drugs in clinical practice exert their action by interacting with mitochondrial pathways. This review attempts to focus on the various groups of drugs which act on mitochondria and are utilized for therapy of conditions like cancer, diabetes mellitus, neurodegeneration and so on.

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Troglitazone, but not rosiglitazone, damages mitochondrial DNA and induces mitochondrial dysfunction and cell death in human hepatocytes

Cited by 88 publications

References 36 publications

Utility of human hepatocyte spheroids for evaluation of hepatotoxicity

Utility of human hepatocyte spheroids for evaluation of hepatotoxicity

Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver

Drugs acting on mitochondrial pathways

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