Nevirapine induced mitochondrial dysfunction in HepG2 cells

Abstract

Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor frequently used in combination with other antiretroviral agents for highly active antiretroviral therapy (HAART) of patients infected with the human immunodeficiency virus type 1 (HIV-1). However NVP can cause serious, life-threatening complications. Hepatotoxicity is one of the most severe adverse effects, particularly in HIV patients with chronic hepatitis C virus co-infection as these patients can develop liver toxicity after a relatively short course of treatment. However, the mechanism of NVP-associated hepatotoxicity remains unclear. This study sought to investigate the effect of NVP on protein expression in liver cells using a proteomic approach. HepG2 cells were treated or not treated with NVP and proteins were subsequently resolved by two-dimensional gel electrophoresis. A total of 33 differentially regulated proteins were identified, of which nearly 40% (13/33) were mitochondrial proteins. While no obvious differences were observed between NVP treated and untreated cells after staining mitochondria with mitotracker, RT-PCR expression analysis of three mitochondrially encoded genes showed all were significantly up-regulated in NVP treated cells. Mitochondrial dysfunction was observed in response to treatment even with slightly sub-optimal therapeutic treatment concentrations of NVP. This study shows that NVP induces mitochondrial dysregulation in HepG2 cells.

Delay of cell growth and loss of stemness by inhibition of reverse transcription in human mesenchymal stem cells derived from dental tissue

“…However, the several side effects, such as rash, nausea, fatigue, headache, vomiting, diarrhoea, and pain, have been reported after oral intake of NVP (Chowta et al 2018). It has been further reported that in vitro direct treatment of NVP is induced to the induction of hepatotoxicity by mitochondrial dysfunction and apoptosis in HepG2 cells (Wongtrakul J, et al 2016; Paemanee et al 2017). The treatment of NVP has also been demonstrated to delay cell growth in the various types of cells, especially cancer cells.…”

Phosphoproteomic analysis of dengue virus infected U937 cells and identification of pyruvate kinase M2 as a differentially phosphorylated phosphoprotein

“…Two-dimensional gel electrophoresis separation of 300 μg of enriched phosphoproteins was performed independently in triplicate as described previously 54 .…”

“…Protein spots showing differential phosphorylation were removed and subjected to in-gel tryptic digestion and mass spectroscopic analysis essentially as described previously 54 . The MS/MS spectrometry data were searched against the NCBI database using the MASCOT search engine, as described elsewhere 54 . Functional analysis of identified phosphoproteins was performed using STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) version 11.0.…”

“…showing differential phosphorylation were removed and subjected to in-gel tryptic digestion and mass spectroscopic analysis essentially as described previously 54 . The MS/MS spectrometry data were searched against the NCBI database using the MASCOT search engine, as described elsewhere 54 .…”

The application of omics-based human liver platforms for investigating the mechanism of drug-induced hepatotoxicity in vitro

“…HepG2 cells, due to their high mitochondrial DNA and organelles contents, remain a model of choice for the study of compound-induced mitochondrial dysfunction (Poloznikov et al 2018). Applied transcriptomic and proteomic analyses to this cell model, Jiang et al (2015a) and Paemanee et al (2017) explained the mechanisms of mitochondrial dysfunction associated with APAP and nevirapine (NVP) administrations. Using a HepG2-based in vitro cytokine synergy model, an attempt has been made to investigate the relationship between inflammation and drug idiosyncrasy (Jiang et al 2017).…”