Clopidogrel-induced liver failure

Monteiro, Patrícia Howell; Pinheiro, Luís Campos; Alvoeiro, Lourdes; Lucas, Margarida; Victorino, Rui

doi:10.1258/shorts.2011.010111

Cited by 5 publications

(2 citation statements)

References 9 publications

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“…TPMT selectively methylates thiopurine compounds while TMT is selective for aliphatic thiol substrates 4 – 6 . Both enzymes exhibit highly variable activity in vivo which can lead to toxicity for thiol-containing drugs that undergo methylation, such as azathioprine and the active metabolite of clopidogrel 7 – 14 . While TPMT has been extensively characterized, TMT is a putative microsomal enzyme that selectively methylates aliphatic thiols, with potential substrates including hydrogen sulfide (H 2 S), captopril, 7α-thiospironolactone, d - and l -penicillamine, and the active metabolites of prasugrel, clopidogrel, and ziprasidone 6 , 15 – 20 .…”

Section: Introductionmentioning

confidence: 99%

Human METTL7B is an alkyl thiol methyltransferase that metabolizes hydrogen sulfide and captopril

Maldonato

Russell

Totah

2021

Sci Rep

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Methylation of alkyl thiols is a biotransformation pathway designed to reduce thiol reactivity and potential toxicity, yet the gene and protein responsible for human alkyl thiol methyltransferase (TMT) activity remain unknown. Here we demonstrate with a range of experimental approaches using cell lines, in vitro systems, and recombinantly expressed enzyme, that human methyltransferase-like protein 7B (METTL7B) catalyzes the transfer of a methyl group from S-adenosyl-l-methionine (AdoMet) to hydrogen sulfide (H2S) and other exogenous thiol small molecules. METTL7B gene modulation experiments, including knockdown in HepG2 cells and overexpression in HeLa cells, directly alter the methylation of the drug captopril, a historic probe substrate for TMT activity. Furthermore, recombinantly expressed and purified wild-type METTL7B methylates several thiol compounds, including H2S, 7α-thiospironolactone, l-penicillamine, and captopril, in a time- and concentration-dependent manner. Typical for AdoMet-dependent small molecule methyltransferases, S-adenosyl-l-homocysteine (AdoHcy) inhibited METTL7B activity in a competitive fashion. Similarly, mutating a conserved aspartate residue, proposed to anchor AdoMet into the active site, to an alanine (D98A) abolished methylation activity. Endogenous thiols such as glutathione and cysteine, or classic substrates for other known small molecule S-, N-, and O-methyltransferases, were not substrates for METTL7B. Our results confirm, for the first time, that METTL7B, a gene implicated in multiple disease states including rheumatoid arthritis and breast cancer, encodes a protein that methylates small molecule alkyl thiols. Identifying the catalytic function of METTL7B will enable future pharmacological research in disease pathophysiology where altered METTL7B expression and, potentially H2S levels, can disrupt cell growth and redox state.

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Section: Introductionmentioning

confidence: 99%

Human METTL7B is an alkyl thiol methyltransferase that metabolizes hydrogen sulfide and captopril

Maldonato

Russell

Totah

2021

Sci Rep

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“…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 ). However, the mechanisms of clopidogrel-associated hepatotoxicity have not been fully elucidated.…”

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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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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