The mechanism and risk factors of clopidogrel-induced liver injury

Zhai, Yiran; Wang, Lili; Yang, Fan; Guo, Feng; Feng, Shan; Cui, Tianyi; An, Li; He, Xiaolong

doi:10.3109/01480545.2015.1122606

Cited by 11 publications

(11 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mechanisms underlying clopidogrel-induced hepatotoxicity have not been fully elucidated. The general mechanisms of hepatotoxicity involve cellular accumulation of reactive oxygen species and opening of the mitochondrial permeability transition pore, leading to a release of cytochrome c into the cytoplasm, which is a key event in apoptosis (Zahno et al, 2013 ; Zhai et al, 2016 ), supporting our finding that clopidogrel-induced hepatotoxicity is directly related to apoptosis. Moreover, considering that this adverse effect is idiosyncratic (Kapila et al, 2015 ), understanding the regulatory mechanism will promote future studies attempting to validate the epigenetic mechanism involved in drug-induced hepatotoxicity.…”

Section: Discussionsupporting

confidence: 88%

“…In a previous study, 10 and 100 μM clopidogrel were shown to be toxic to primary human hepatocytes when combined with rifampicin (an inducer of CYP3A4) and to HepG2 cells overexpressing CYP3A4 (Zahno et al, 2013 ). In addition, high concentrations of clopidogrel (100 and 300 μM) were significantly toxic to primary rat hepatocytes and HepG2 cells co-incubated with recombinant CYP2B6 and CYP2C19 (Zhai et al, 2016 ). These effects have been attributed to 2-oxo-clopidogrel, a bioactive metabolite, produced by CYP enzymes (Maffrand, 2012 ; Zhai et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, high concentrations of clopidogrel (100 and 300 μM) were significantly toxic to primary rat hepatocytes and HepG2 cells co-incubated with recombinant CYP2B6 and CYP2C19 (Zhai et al, 2016 ). These effects have been attributed to 2-oxo-clopidogrel, a bioactive metabolite, produced by CYP enzymes (Maffrand, 2012 ; Zhai et al, 2016 ). In contrast, it has been shown that high concentration (100 μM) of clopidogrel and its major inactive metabolite (CAM) are not toxic to wild-type HepG2 cells (Zahno et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

“…It is likely that downregulation of EIF4G2 led to the increased DNA fragmentation and apoptosis observed in response to clopidogrel. This cytotoxic mechanism may be associated with an accumulation of reactive oxygen species and mitochondrial damage in the presence of the clopidogrel (Zahno et al, 2013 ; Zhai et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Modulation of miR-26a-5p and miR-15b-5p Exosomal Expression Associated with Clopidogrel-Induced Hepatotoxicity in HepG2 Cells

et al. 2017

View full text Add to dashboard Cite

Clopidogrel is an essential antiplatelet drug used to prevent thrombosis complications associated with atherosclerosis. However, hepatotoxicity is a potential adverse effect related to clopidogrel therapy. Exosome-derived miRNAs may be useful for improved monitoring of drug response and hepatotoxicity risk. In the present study, the expression of several exosomal miRNAs (miR-26a-5p, miR-145-5p, miR-15b-5p, and miR-4701-3p) and cell-derived mRNA targets (PLOD2, SENP5, EIF4G2, HMGA2, STRADB, and TLK1) were evaluated in HepG2 cells treated with clopidogrel (6.25, 12.5, 25, 50, and 100 μM) for 24 and 48 h. Then, clopidogrel cytotoxicity was evaluated by analyzing DNA fragmentation and the cell cycle profile using flow cytometry. Differential expression of exosome-derived miRNAs and cell-derived mRNAs was analyzed by RT-qPCR. Exposure of HepG2 cells to high concentrations of clopidogrel (50 and 100 μM) for 24 h caused significant DNA fragmentation (17.6 and 44.4%, respectively; p < 0.05) and 48 h (26.8 and 48.9%, respectively; p < 0.05), indicating cellular toxicity. Upregulation of miR-26a-5p and downregulation of miR-15b-5p was observed in cells exposed to 100 μM clopidogrel for 24 and 48 h. The miR-26a-5p target mRNAs HMGA2, EIF4G2, STRADB, and SENP5 were downregulated in HepG2 cells following exposure to cytotoxic concentrations of clopidogrel (50 and 100 μM) for 24 h, and HMGA2 levels remained low after 48 h of treatment. TLK1, a target of miR-15b-5p, was downregulated by 50 and 100 μM clopidogrel at 24 h. In conclusion, our results suggest that exposure to high concentrations of clopidogrel modulates the expression of exosomal miR-26a-5p and miR-15b-5p and their target mRNAs in HepG2 cells. Dysregulation of these miRNAs maybe modulate the regulatory pathways involved in clopidogrel-induced liver injury.

show abstract

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Modulation of miR-26a-5p and miR-15b-5p Exosomal Expression Associated with Clopidogrel-Induced Hepatotoxicity in HepG2 Cells

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Clopidogrel, a platelet aggregation inhibitor, is a prodrug that is metabolized into an active metabolite mainly by CYP2C19 (Wallentin et al, 2010;Gillette et al, 2016;Kiss et al, 2018). In a study using primary rat hepatocytes and HepG2 cells, Zhai et al (2016) revealed that the hepatocellular toxicity of clopidogrel is associated with CYP2C19-mediated metabolism. Therefore, we expected that CYP2C19-KO HLCs would exhibit a different response to clopidogrel as compared with WT HLCs.…”

Section: Resultsmentioning

confidence: 99%

Modeling of Hepatic Drug Metabolism and Responses in CYP2C19 Poor Metabolizer Using Genetically Manipulated Human iPS cells

et al. 2019

View full text Add to dashboard Cite

Cytochrome P450 family 2 subfamily C member 19 (CYP2C19), in liver, plays important roles in terms of drug metabolism. It is known that CYP2C19 poor metabolizers (PMs) lack CYP2C19 metabolic capacity. Thus, unexpected drug-induced liver injury or decrease of drug efficacy would be caused in CYP2C19 substrate-treated CYP2C19 PMs. However, it is difficult to evaluate the safety and effectiveness of drugs and candidate compounds for CYP2C19 PMs because there is currently no model for this phenotype. Here, using human induced pluripotent stem cells (human iPS cells) and our highly efficient genome-editing and hepatocyte differentiation technologies, we generated CYP2C19-knockout human iPS cell-derived hepatocyte-like cells (CYP2C19-KO HLCs) as a novel CYP2C19 PM model for drug development and research. The gene expression levels of hepatocyte markers were similar between wild-type iPS cell-derived hepatocyte-like cells (WT HLCs) and CYP2C19-KO HLCs, suggesting that CYP2C19 deficiency did not affect the hepatic differentiation potency. We also examined CYP2C19 metabolic activity by measuring S-mephenytoin metabolites using ultraperformance liquid chromatography-tandem mass spectrometry. The CYP2C19 metabolic activity was almost eliminated by CYP2C19 knockout. Additionally, we evaluated whether clopidogrel (CYP2C19 substrate)-induced liver toxicity could be predicted using our model. Unexpectedly, there was no significant difference in cell viability between clopidogrel-treated WT HLCs and CYP2C19-KO HLCs. However, the cell viability in clopidogreland ketoconazole (CYP3A4 inhibitor)-treated CYP2C19-KO HLCs was significantly enhanced as compared with that in clopidogreland DMSO-treated CYP2C19-KO HLCs. This result suggests that CYP2C19-KO HLCs can predict clopidogrel-induced liver toxicity. We succeeded in generating CYP2C19 PM model cells using human iPS cells and genome-editing technologies for pharmaceutical research. SIGNIFICANCE STATEMENT Although unexpected drug-induced liver injury or decrease of drug efficacy would be caused in CYP2C19 substrate-treated CYP2C19 poor metabolizers, it is difficult to evaluate the safety and effectiveness of drugs and candidate compounds for CYP2C19 poor metabolizers because there is currently no model for this phenotype. Using human iPS cells and our highly efficient genome editing and hepatocyte differentiation technologies, we generated CYP2C19-knockout human iPS cell-derived hepatocyte-like cells as a novel CYP2C19 poor metabolizer model for drug development and research.

show abstract

Drug‐Metabolizing Enzymes and Drug Toxicity

2021

Transporters and Drug‐Metabolizing Enzymes in Drug Toxicity

View full text Add to dashboard Cite

The mechanism and risk factors of clopidogrel-induced liver injury

Abstract: High activities of CYP2C19 and CYP2B6 are the risk factors for hepatocellular toxicity of CLP.

Cited by 11 publications

References 31 publications

Modulation of miR-26a-5p and miR-15b-5p Exosomal Expression Associated with Clopidogrel-Induced Hepatotoxicity in HepG2 Cells

Modulation of miR-26a-5p and miR-15b-5p Exosomal Expression Associated with Clopidogrel-Induced Hepatotoxicity in HepG2 Cells

Modeling of Hepatic Drug Metabolism and Responses in CYP2C19 Poor Metabolizer Using Genetically Manipulated Human iPS cells

Drug‐Metabolizing Enzymes and Drug Toxicity

Contact Info

Product

Resources

About