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Unveiling the molecular basis of paracetamol-induced hepatotoxicity: Interaction of -acetyl--benzoquinone imine with mitochondrial succinate dehydrogenase. | LitMetric

AI Article Synopsis

  • - Background: NAPQI, a toxic byproduct of paracetamol, can accumulate in the liver, leading to damage by depleting glutathione and disrupting mitochondrial function, which increases superoxide production and decreases ATP levels.
  • - Methods: Researchers used techniques like molecular docking and simulations, along with protein interaction analysis, to explore how NAPQI binds to succinate dehydrogenase (SDH), a mitochondrial enzyme, under realistic cellular conditions by including a lipid membrane.
  • - Results: The study found that both paracetamol and NAPQI have strong binding affinities for SDH, with NAPQI showing slightly more stability, helping to predict the mechanisms behind paracetamol's liver toxicity and identify

Article Abstract

Background And Aim: -acetyl--benzoquinoneimine (NAPQI), a toxic byproduct of paracetamol (Acetaminophen, APAP), can accumulate and cause liver damage by depleting glutathione and forming protein adducts in the mitochondria. These adducts disrupt the respiratory chain, increasing superoxide production and reducing ATP. The goal of this study was to provide computational proof that succinate dehydrogenase (SDH), a subunit of complex II in the mitochondrial respiratory chain, is a favorable binding partner for NAPQI in this regard.

Method: Molecular docking, molecular dynamics simulation, protein-protein interaction networks (PPI), and KEGG metabolic pathway analysis were employed to identify binding characteristics, interaction partners, and their associations with metabolic pathways. A lipid membrane was added to the experimental apparatus to mimic the natural cellular environment of SDH. This modification made it possible to develop a context for investigating the role and interactions of SDH within a cellular ecosystem that was more realistic and biologically relevant.

Result: The molecular binding affinity score for APAP and NAPQI with SDH was predicted -6.5 and -6.7 kcal/mol, respectively. Furthermore, RMSD, RMSF, and Rog from the molecular dynamics simulations study revealed that NAPQI has slightly higher stability and compactness compared to APAP at 100 ns timeframe with mitochondrial SDH.

Conclusion: This study serves to predict the mechanistic process of paracetamol toxicity by using different computational approaches. In addition, this study will provide information about the drug target against APAP hepatotoxicity.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11098724PMC
http://dx.doi.org/10.1016/j.bbrep.2024.101727DOI Listing

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