Characterizing the mechanism of thiazolidinedione-induced hepatotoxicity: An in vitro model in mitochondria

Hu, Dan; Wu, Cathy; Li, Zejun; Liu, Yue; Fan, Xing; Wang, Quanjun; Ding, Ru

doi:10.1016/j.taap.2015.02.018

Cited by 45 publications

(40 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, TZDs demonstrated varying degrees of hepatotoxicity in an in vitro model, with troglitazone exhibiting the highest mitochondrial toxicity, followed by rosiglitazone and then pioglitazone. TZD-induced hepatotoxicity may involve alterations in mitochondrial respiratory function, changes in membrane permeability, and mitochondrial structural damage [69]. An in vitro study demonstrated that both rosiglitazone and pioglitazone at supra-physiological concentrations (100 μM) directly inhibited mitochondrial respiratory chain complex I activity and cell respiration in rat skeletal muscles [70].…”

Section: Ppars Modulate Mitochondrial Functionmentioning

confidence: 99%

PPARs modulate cardiac metabolism and mitochondrial function in diabetes

et al. 2017

View full text Add to dashboard Cite

Diabetic cardiomyopathy is a major complication of diabetes mellitus (DM). Currently, effective treatments for diabetic cardiomyopathy are limited. The pathophysiology of diabetic cardiomyopathy is complex, whereas mitochondrial dysfunction plays a vital role in the genesis of diabetic cardiomyopathy. Metabolic regulation targeting mitochondrial dysfunction is expected to be a reasonable strategy for treating diabetic cardiomyopathy. Peroxisome proliferator-activated receptors (PPARs) are master executors in regulating glucose and lipid homeostasis and also modulate mitochondrial function. However, synthetic PPAR agonists used for treating hyperlipidemia and DM have shown controversial effects on cardiovascular regulation. This article reviews our updated understanding of the beneficial and detrimental effects of PPARs on mitochondria in diabetic hearts.

show abstract

Section: Ppars Modulate Mitochondrial Functionmentioning

confidence: 99%

PPARs modulate cardiac metabolism and mitochondrial function in diabetes

et al. 2017

View full text Add to dashboard Cite

show abstract

“…A major non-metabolic toxicity factor is via effects on mitochondria resulting in depletion of ATP and release of cytochrome c, which induces cell death via apoptosis (Tirmenstein et al 2002; Hu et al 2015). Lipid peroxidation and PPARγ-dependent steatosis are also mediated by troglitazone.…”

Section: Idiosyncratic Toxicity and Toxicity Profiles Of Selected Tramentioning

confidence: 99%

Evidence-based selection of training compounds for use in the mechanism-based integrated prediction of drug-induced liver injury in man

Dragović¹,

Vermeulen²,

Gerets

et al. 2016

Arch Toxicol

View full text Add to dashboard Cite

The current test systems employed by pharmaceutical industry are poorly predictive for drug-induced liver injury (DILI). The ‘MIP-DILI’ project addresses this situation by the development of innovative preclinical test systems which are both mechanism-based and of physiological, pharmacological and pathological relevance to DILI in humans. An iterative, tiered approach with respect to test compounds, test systems, bioanalysis and systems analysis is adopted to evaluate existing models and develop new models that can provide validated test systems with respect to the prediction of specific forms of DILI and further elucidation of mechanisms. An essential component of this effort is the choice of compound training set that will be used to inform refinement and/or development of new model systems that allow prediction based on knowledge of mechanisms, in a tiered fashion. In this review, we focus on the selection of MIP-DILI training compounds for mechanism-based evaluation of non-clinical prediction of DILI. The selected compounds address both hepatocellular and cholestatic DILI patterns in man, covering a broad range of pharmacologies and chemistries, and taking into account available data on potential DILI mechanisms (e.g. mitochondrial injury, reactive metabolites, biliary transport inhibition, and immune responses). Known mechanisms by which these compounds are believed to cause liver injury have been described, where many if not all drugs in this review appear to exhibit multiple toxicological mechanisms. Thus, the training compounds selection offered a valuable tool to profile DILI mechanisms and to interrogate existing and novel in vitro systems for the prediction of human DILI.

show abstract

“…The thiazolidinedione (TZDs) are used in patients with diabetes to help improve insulin resistance and glucose homeostasis. Furthermore, these drugs are known as peroxisome proliferator-activated receptor gamma (PPARγ) agonists [1][2][3][4]. These synthetic compounds are pioglitazone, rosiglitazone, troglitazone and ciglitazone [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…One of the mechanisms by which TZDs cause cytotoxicity is through the generation of ROS. It has been reported that there is a direct relevance between the level of ROS and the degree of cytotoxicity induced by these compounds [2,3,14]. Increased ROS generation induced by some TZDs lead to oxidation of vital components within mitochondria (such as mitochondrial DNA, mtDNA) and also induction of apoptotic signaling [21].…”

Section: Introductionmentioning

confidence: 99%

“…The consequences of mitochondrial inhibition or disruption include the generation of ROS, ATP depletion, and eventually cell death (apoptosis/necrosis). Mitochondria as one of the important organelles in eukaryotic cells are involved in important physiological processes including the generation of free radicals, energy production and cell death [2,3,14,19,22]. Therefore, mitochondrial dysfunction can be dangerous for different cells and organs due to insufficient ATP generation and excessive level of ROS [18].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Toxicity of Pioglitazone on Mitochondria Isolated from Brain and Heart: An Analysis for Probable Drug-Induced Neurotoxicity and Cardiotoxicity

et al. 2020

View full text Add to dashboard Cite

Pioglitazone (PG) is one of the thiazolidinedione (TZDs) drugs used in diabetic patients. TZDs are known as peroxisome proliferator-activated receptor gamma (PPARγ) agonists. Mitochondria are considered as one of the targets of these drugs. The mechanisms of the effect of PG on mitochondria are not well understood. In this study, we investigated the effect of PG on mitochondria isolated from brain and heart. Mitochondrial parameters such as succinate dehydrogenase (SDH) activity, reactive oxygen species (ROS) generation, collapse in mitochondrial membrane potential (MMP), mitochondrial swelling and cytochrome c release were evaluated. The results showed that PG at concentrations of 12.5, 25 and 50 µg/ml increased the generation of ROS, the collapse of MMP, mitochondrial swelling and the release of cytochrome c in mitochondria isolated from both brain and heart tissues. The underlying mechanisms of PG induced neuro-toxicity and cardio-toxicity may be associated with changes in mitochondrial function, ROS generation (oxidative stress), and changes in the mitochondrial membrane.

show abstract

Characterizing the mechanism of thiazolidinedione-induced hepatotoxicity: An in vitro model in mitochondria

Cited by 45 publications

References 34 publications

PPARs modulate cardiac metabolism and mitochondrial function in diabetes

PPARs modulate cardiac metabolism and mitochondrial function in diabetes

Evidence-based selection of training compounds for use in the mechanism-based integrated prediction of drug-induced liver injury in man

Toxicity of Pioglitazone on Mitochondria Isolated from Brain and Heart: An Analysis for Probable Drug-Induced Neurotoxicity and Cardiotoxicity

Contact Info

Product

Resources

About