Studies on toxicity of antitubercular drugs namely isoniazid, rifampicin, and pyrazinamide in an in vitro model of HepG2 cell line

Abstract

Antitubercular drugs (ATT) are known to be majorly metabolized and detoxified in liver by both Phase I and Phase II group of drug metabolizing enzymes. These drugs as well as their metabolites are toxic and during this process cause injury to liver. In this study, we have investigated the in vitro hepatotoxic potential of both individual as well as combination ATT drugs using an in vitro model of human hepatocellular carcinoma cell line (HepG2). The cells were treated with varied concentrations of ATT drugs namely isoniazid (INH), rifampicin (RIF), and pyrazinamide (PYZ) for different durations. Cytotoxicity assay using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide) as well as morphological analysis using phase contrast microscopy have shown that concentrations used were not cytotoxic. However, pretreatment with sub-cytotoxic concentrations of INH and PYZ increased the toxicity with the same drugs. This report corroborates the clinical finding that long-term treatment as well combination drug therapy with ATT induces hepatotoxicity rather than individual drugs.

Association of N‐acetyltransferase 2 and cytochrome P450 2E1 gene polymorphisms with antituberculosis drug‐induced hepatotoxicity in Western India

“…Hepatotoxicity due to long‐term use of multidrug therapy for TB is a serious outcome, as these drugs exhibit toxicity in a synergistic manner . In the present study, percentage of females with SA phenotype was higher compared with IA and RA phenotypes (data not shown).…”

Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment

“…Despite the fact that INH has been widely used as a first-line antitubercular agent (2,3), its therapeutic value is usually accompanied by severe hepatotoxicity and lethal hepatic injury (4,5). Although the pathophysiology of INH-induced liver injury might vary, the toxicity features of the drug, including hepatocellular steatosis, necrosis, and inflammatory infiltration, are nearly consistent (6,7).…”

Adverse Outcome Pathway on Protein Alkylation Leading to Liver Fibrosis

“…Further knowledge was gathered by looking for mechanistic data of other chemicals which are known inducers of liver fibrosis, namely Thioacetamide (Akhtar and Nadeem Sheikh, 2013;Altomonte et al, 2013;Amin al., 2013;Chilakapati et al, 2005;Hajovsky et al, 2012;Ide et al, 2003;Kang, 2008;Kim et al, 2013;Ledda-Columbano et al, 1991;Low et al, 2004;Nafees et al, 2013;Sarma et al, 2012;Shirai et al, 2013;Staňková et al, 2010;Sun et al, 2000;Waters et al, 2005), Amiodarone (Cimic and Sirintrapun, 2013;Felser et al, 2013;Golli-Bennour et al, 2012;Isomoto et al, 2004;Kicker et al, 2012;Lu et al, 2013: Nasser et al, 2013, Methotrexate (AlAli et al, 2005;Al-Motabagani, 2006;Belinsky et al, 2007;Fathi et al, 2002;Hall et al, 1991;Hytiroglou et al, 2004;Lindsay K et al, 2009), Isoniazid (Bhadauria et al, 2007;Schwab and Tuschl, 2003;Singh et al, 2010;Tostmann et al, 2008), Dimethyl Nitrosamine (George et al, 2003;George, 2001;Ju et al, 2013;Usunomena et al, 2012), Ethanol (Das et al, 2010;…”