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.

Quercetin protected against isoniazide‐induced HepG2 cell apoptosis by activating the SIRT1/ERK pathway

“…The complex mechanisms of INH‐induced hepatotoxicity involve metabolism, necrosis, oxidative stress, lipid peroxidation, inflammation, and apoptosis . To date, apoptosis has been recognized as an important factor responsible for INH‐induced hepatotoxicity.…”

High-Dose Paraquat Induces Human Bronchial 16HBE Cell Death and Aggravates Acute Lung Intoxication in Mice by Regulating Keap1/p65/Nrf2 Signal Pathway

“…ROS-mediated autophagy-induced cell death also played an important role in PQ-induced cell intoxication [ 11 ], but the mechanisms are still unclear. The activation of Keap1/Nrf2 signal pathway was demonstrated to regulate ROS generation and inflammatory reactions [ 12 , 18 , 19 ], and p65 was capable of binding Keap1 and potentially participated in the inactivation of Keap1/Nrf2 signal pathway [ 17 ]. However, it is still unknown whether PQ induced cell intoxication and inflammatory reactions by regulating p65 and Keap1/Nrf2 signal pathway, and the influences of p65 on Keap1/Nrf2 signal pathway still need to be elucidated.…”

“…Keap1 physically associates with p65 [ 17 ], but it is still unclear whether p65 involves in the activation of Keap1/Nrf2 signal pathway. The activation of Keap1/Nrf2 signal pathway is also reported to regulate ROS-regulated cell autophagy [ 12 ] and apoptosis [ 18 ]. In addition, Nrf2 has also been reported to modulate inflammatory reactions [ 19 ].…”

Dysregulation of NRF2 in Cancer: from Molecular Mechanisms to Therapeutic Opportunities

“…Interestingly, it has been suggested recently that the hepatotoxicity caused by antitubercular drugs is attributed to inhibition of NRF2. In the Hep3B hepatoma cell line, INH prevented nuclear translocation of NRF2 by inhibition of extracellular signal-regulated kinase 1 (ERK1) phosphorylation, which leads to the oxidative stress and apoptosis ( Verma et al ., 2015 ). In addition, INH effectively inhibited the mRNA expression of NRF2-inducible genes in mouse preadipocyte 3T3-L1 cells ( Chen et al ., 2013 ).…”