title: Isoniazid prevents Nrf2 translocation by inhibiting ERK1 phosphorylation and induces oxidative stress and apoptosis.
abstract: Isoniazid is used either alone or in combination with other drugs for the treatment of tuberculosis. It is also used for the prevention of tuberculosis. Chronic treatment of Isoniazid may cause severe liver damage leading to acute liver failure. The mechanism through which Isoniazid causes liver damage is investigated. Isoniazid treatment generates reactive oxygen species and induces apoptosis in Hep3B cells. It induces antioxidative and apoptotic genes leading to increase in mRNA expression and protein levels in Hep3B cells. Whole genome expression analysis of Hep3B cells treated with Isoniazid has resulted in differential expression of various genes playing prime role in regulation of apoptotic, antioxidative, DNA damage, cell signaling, cell proliferation and differentiation pathways. Isoniazid increased cytosolic Nrf2 protein level while decreased nuclear Nrf2 protein level. It also decreased ERK1 phosphorylation and treatment of Hep3B cells with ERK inhibitor followed by Isoniazid resulting in increased apoptosis in these cells. Two dimensional gel electrophoresis results have also shown differential expression of various protein species including heat shock proteins, proteins playing important role in oxidative stress, DNA damage, apoptosis, cell proliferation and differentiation. Results suggest that Isoniazid induces apoptosis through oxidative stress and also prevents Nrf2 translocation into the nucleus by reducing ERK1 phosphorylation thus preventing cytoprotective effect.
authors.affiliation: PCS 103 Genotoxicity Lab, Division of Toxicology, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India. Electronic address: ajeetsonicdri@gmail.com.
authors.forename: Ajeet Kumar
authors.initials: AK
authors.lastname: Verma
authors.affiliation: PCS 103 Genotoxicity Lab, Division of Toxicology, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India. Electronic address: artiyadav.srm@gmail.com.
authors.forename: Arti
authors.initials: A
authors.lastname: Yadav
authors.affiliation: PCS 103 Genotoxicity Lab, Division of Toxicology, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India. Electronic address: jayantdewangan@gmail.com.
authors.forename: Jayant
authors.initials: J
authors.lastname: Dewangan
authors.affiliation: PCS 103 Genotoxicity Lab, Division of Toxicology, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India. Electronic address: sarvendravs@gmail.com.
authors.forename: Sarvendra Vikram
authors.initials: SV
authors.lastname: Singh
authors.affiliation: Plant Molecular Biology Division, CSIR-National Botanical Research Institute, Rana Pratap Marg, Lucknow 226001, India. Electronic address: manisha.nbri@gmail.com.
authors.forename: Manisha
authors.initials: M
authors.lastname: Mishra
authors.affiliation: Plant Molecular Biology Division, CSIR-National Botanical Research Institute, Rana Pratap Marg, Lucknow 226001, India. Electronic address: pradhyumnasingh@hotmail.com.
authors.forename: Pradhyumna Kumar
authors.initials: PK
authors.lastname: Singh
authors.affiliation: PCS 103 Genotoxicity Lab, Division of Toxicology, CSIR-Central Drug Research Institute, B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India. Electronic address: skrath@cdri.res.in.
authors.forename: Srikanta Kumar
authors.initials: SK
authors.lastname: Rath
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology*; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000995:Antitubercular Agents; D006360:Heat-Shock Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D048052:Mitogen-Activated Protein Kinase 3; D007538:Isoniazid
keywords: Differential expression; ERK inhibitor; Isoniazid; Oxidative stress; Phosphorylation