Triptolide induces p53-dependent cardiotoxicity through mitochondrial membrane permeabilization in cardiomyocytes

Xi, Yue; Wang, Wenwen; Wang, Li; Pan, Jinyan; Cheng, Yisen; Shen, Feihai; Huang, Zhiying

doi:10.1016/j.taap.2018.07.011

Cited by 25 publications

(17 citation statements)

References 38 publications

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“…These results indicate that almost all cytotoxic mechanism events or stress responses observed in this experiment upon treatment with TP are dependent on inhibition of cell viability. That may explain why various mechanisms, including oxidative stress (Yang, Ren, Zhuo, Ananda, & Liu, ), MMP dysfunction (Su et al, ; Xi et al, ; You et al, ) and DNA damage, have been reported (Chueh et al, ). Indeed, these cytotoxic events exist during TP‐induced liver injury, but they are not the specific toxic event of TP exposure.…”

Section: Discussionmentioning

confidence: 99%

High‐content analysis boosts identification of the initial cause of triptolide‐induced hepatotoxicity

Zheng¹,

Wang

Wei³

et al. 2019

J of Applied Toxicology

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Triptolide (TP) has been widely used in China for more than 40 years as an immunosuppressive agent. Recently, serious concerns have been raised over TP-induced liver injury, though the real hepatotoxic mechanism is still unclear, particularly in terms of the initial cause. To our knowledge, this study is the first to screen systematically the mechanism of TP-induced toxicity through a global cytotoxicity profile high-content analysis using three independent cytotoxic assay panels with multiple endpoints of cytotoxicity, including cell loss, mitochondrial membrane potential, nuclear membrane permeability, manganese superoxide dismutase, phosphorylated gamma-H2AX, light chain 3B, lysosome, reactive oxygen species and glutathione. We assessed nine parameters and four stress response pathway models by labeling nuclear factor erythroid 2-related factor 2, activating transcription factor 6, hypoxia inducible factor 1α and nuclear factor κB and found that all testing parameters except glutathione and manganese superoxide dismutase showed concentration-and time-dependent changes, as well as increased cell loss after TP treatment. Considering that RNA polymerase II is the molecular target of TP, we quantified transcription from inducible genes, bromodeoxyuridine incorporation, and expression from transiently transfected green fluorescence protein plasmids in HepG2 cells. The results show that inhibition of global transcription by TP took place at earlier times and at lower concentrations than those observed for cell death.Therefore, global transcriptional suppression and the cell dysfunction it drives play a central role in TP-induced hepatotoxicity. This provides valuable information for the safe use of TP in the clinic. KEYWORDShigh-content analysis, liver injury, RNAPII, TP-induced hepatotoxicity, triptolide

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Section: Discussionmentioning

confidence: 99%

High‐content analysis boosts identification of the initial cause of triptolide‐induced hepatotoxicity

Zheng¹,

Wang

Wei³

et al. 2019

J of Applied Toxicology

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“…cTnI and plasma granulase B in SD rats were significantly increased by water decoction of Tripterygium wilfordii. Studies on the cardiotoxicity of triptolide and Radix Aconiti extract revealed that serum cTnI level increased after administration (Lin et al, 2011;Xi et al, 2018). Acute aconitine intoxication manifested as remarkable elevation in serum CK, CK-MB, and cTnI levels (Lin et al, 2011).…”

Section: Biomarkersmentioning

confidence: 99%

“…Experiments in vivo and in vitro showed that triptolide permeabilized the outer mitochondrial membrane and promoted the opening of mPTP, thereby causing mitochondrial dysfunction and apoptosis (Wang et al, 2016b;Xi et al, 2018). In addition, CMM that has cardiotoxicity can also indirectly damage myocardial mitochondria by regulating mitochondrial outer membrane integrity, mitochondrial dynamics, mitochondria-dependent apoptosis genes, and proteins.…”

Section: Mitochondrial Toxicitymentioning

confidence: 99%

Risk Compounds, Preclinical Toxicity Evaluation, and Potential Mechanisms of Chinese Materia Medica–Induced Cardiotoxicity

Zhou

Cao

et al. 2021

Front. Pharmacol.

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Chinese materia medica (CMM) has been applied for the prevention and treatment of diseases for thousands of years. However, arrhythmia, myocardial ischemia, heart failure, and other cardiac adverse reactions during CMM application were gradually reported. CMM-induced cardiotoxicity has aroused widespread attention. Our review aimed to summarize the risk compounds, preclinical toxicity evaluation, and potential mechanisms of CMM-induced cardiotoxicity. All relevant articles published on the PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases for the latest twenty years were searched and manually extracted. The risk substances of CMM-induced cardiotoxicity are relatively complex. A single CMM usually contains various risk compounds, and the same risk substance may exist in various CMM. The active and risk substances in CMM may be transformed into each other under different conditions, such as drug dosage, medication methods, and body status. Generally, the risk compounds of CMM-induced cardiotoxicity can be classified into alkaloids, terpenoids, steroids, heavy metals, organic acids, toxic proteins, and peptides. Traditional evaluation methods of chemical drug-induced cardiotoxicity primarily include cardiac function monitoring, endomyocardial biopsy, myocardial zymogram, and biomarker determination. In the preclinical stage, CMM-induced cardiotoxicity should be systematically evaluated at the overall, tissue, cellular, and molecular levels, including cardiac function, histopathology, cytology, myocardial zymogram, and biomarkers. Thanks to the development of systematic biology, the higher specificity and sensitivity of biomarkers, such as genes, proteins, and metabolic small molecules, are gradually applied for evaluating CMM-induced cardiotoxicity. Previous studies on the mechanisms of CMM-induced cardiotoxicity focused on a single drug, monomer or components of CMM. The interaction among ion homeostasis (sodium, potassium, and calcium ions), oxidative damage, mitochondrial injury, apoptosis and autophagy, and metabolic disturbance is involved in CMM-induced cardiotoxicity. Clarification on the risk compounds, preclinical toxicity evaluation, and potential mechanisms of CMM-induced cardiotoxicity must be beneficial to guide new CMM development and post-marketed CMM reevaluation.

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“…These results clearly suggest that p53 exerts prooxidant activity and plays a critical role in DOXinduced cardiotoxicity. The prooxidant activity of p53 also has been reported to contribute to triptolide-induced cardiotoxicity in vitro and in vivo, while the p53 antagonist pifithrin-α could ameliorate triptolide-induced apoptosis by suppressing ROS accumulation in primary cardiomyocytes H9c2 cells [41]. Colistin, also known as polymyxin E, could be the first choice in the treatment of infections caused by multidrugresistant Gram-negative bacteria [42]; however, its use is limited by nephrotoxicity and neurotoxicity.…”

Section: Prooxidant Activity Of P53 In Chemical-induced Oxidative Stressmentioning

confidence: 99%

“…Recent research has identified the activities of p53 in the regulation of ROS, along with the upstream and downstream regulators responsible for p53 antioxidant and prooxidant functions. Numerous studies have shown, for example, that p53 can exert prooxidant activity to promote oxidative damage through the regulation of its transcriptional targets, such as p53-inducible genes (PIGs), NCF2/p67phox, a cytosolic subunit of the NADPH oxidase enzyme complex [12,62], p66shc [14,63], and Bax [41] (Figure 1). In contrast, however, several other studies argue that p53 can function as an antioxidant factor to inhibit oxidative stress through the regulation of several redox-related proteins, such as MnSOD [64], GPX1 [58,64], Sestrins [57,65], JNK [36,37], glutaminase 2 [66] ( Figure 2), and TIGAR [67].…”

Section: Mechanisms Of P53 Regulation Of Chemically Induced Oxidativementioning

confidence: 99%

Functional Role of p53 in the Regulation of Chemical-Induced Oxidative Stress

Liu

Fan

et al. 2020

Oxidative Medicine and Cellular Longevity

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The nuclear transcription factor p53, discovered in 1979, has a broad range of biological functions, primarily the regulation of apoptosis, the cell cycle, and DNA repair. In addition to these canonical functions, a growing body of evidence suggests that p53 plays an important role in regulating intracellular redox homeostasis through transcriptional and nontranscriptional mechanisms. Oxidative stress induction and p53 activation are common responses to chemical exposure and are suggested to play critical roles in chemical-induced toxicity. The activation of p53 can exert either prooxidant or antioxidant activity, depending on the context. In this review, we discuss the functional role of p53 in regulating chemical-induced oxidative stress, summarize the potential signaling pathways involved in p53’s regulation of chemically mediated oxidative stress, and propose issues that should be addressed in future studies to improve understanding of the relationship between p53 and chemical-induced oxidative stress.

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Triptolide induces p53-dependent cardiotoxicity through mitochondrial membrane permeabilization in cardiomyocytes

Cited by 25 publications

References 38 publications

High‐content analysis boosts identification of the initial cause of triptolide‐induced hepatotoxicity

High‐content analysis boosts identification of the initial cause of triptolide‐induced hepatotoxicity

Risk Compounds, Preclinical Toxicity Evaluation, and Potential Mechanisms of Chinese Materia Medica–Induced Cardiotoxicity

Functional Role of p53 in the Regulation of Chemical-Induced Oxidative Stress

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