An Idiosyncratic Reaction to Clopidogrel

Kapila, Aaysha; Chhabra, Lovely; Locke, Allison; Patel, Pranav; Khanna, Amit; Reddy, Chakradhar; Young, Mark

doi:10.7812/tpp/14-040

Cited by 5 publications

(3 citation statements)

References 15 publications

(2 reference statements)

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“…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: Discussionmentioning

confidence: 99%

“…The most common adverse effects of clopidogrel treatment include gastrointestinal disorders, bleeding, thrombotic thrombocytopenic purpura, neutropenia, and aplastic anemia (Ochoa-Cortes et al, 2014 ; Kapila et al, 2015 ). Hepatotoxicity is a rare but potentially serious adverse effect related to clopidogrel treatment that can lead to fulminant hepatitis (Goyal et al, 2009 ; Monteiro et al, 2011 ; Zahno et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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“…Table 1 lists reported cases in reverse chronological order. The degree of liver injury has ranged from reversible liver injury and recovery [ 1 – 9 , 11 – 16 ] to acute hepatic failure and death [ 10 ]. Onset of liver injury in these cases ranges between 3 and 180 days [ 1 – 16 ].…”

Section: Discussionmentioning

confidence: 99%