Protective Effect of Bicyclol on Anti-Tuberculosis Drug Induced Liver Injury in Rats

Abstract

The present study was performed to investigate the effect of bicyclol, a synthetic anti-hepatitis drug with anti-oxidative and anti-inflammatory properties, on anti-tuberculosis (anti-TB) drug-induced liver injury and related mechanisms in rats. Bicyclol was given to rats by gavage 2 h before the oral administration of an anti-TB drug once a day for 30 days. Liver injury was evaluated by biochemical and histopathological examinations. Lipid peroxidation, mitochondrial function, and the activity of antioxidants were measured by spectrophotometric methods. Cytokines expression and CYP2E1 activity were determined by ELISA assay and liquid chromatography–tandem mass spectrometry (LC–MS/MS) analysis. The expressions of hepatic CYP2E1 and hepatocyte growth factor (HGF) were assessed by Western blotting. As a result, bicyclol significantly protected against anti-TB drug-induced liver injury by reducing the elevated serum aminotransferases levels and accumulation of hepatic lipids. Meanwhile, the histopathological changes were also attenuated in rats. The protective effect of bicyclol on anti-TB drug-induced hepatotoxicity was mainly due to its ability to attenuate oxidative stress, suppress the inflammatory cytokines and CYP2E1 expression, up-regulate the expression of HGF, and improve mitochondrial function. Furthermore, administration of bicyclol had no significant effect on the plasma pharmacokinetics of the anti-TB drug in rats.

Methionine and vitamin B‐complex ameliorate antitubercular drugs‐induced toxicity in exposed patients

“…Antitubercular medicines like isoniazid produce toxic metabolites, acetyl isoniazid, and hydrazine, which inactivate catalase and superoxide dismutase to induce oxidative stress (Zhai et al 2008). Following an injury to the liver caused by antitubercular medicines, endogenous antioxidant enzymes (CAT, SOD), and the nonenzymatic antioxidant glutathione (GSH) decrease while malondialdehyde (MDA), a marker of lipid peroxidation, increases (Liu et al 2017); corresponding to results from the current research. However, in the test subjects, methionine and vitamin B-complex co-administered with the combination antitubercular medicines corrected these abnormalities compared to patients on only the antitubercular medicines.…”

Protective effect of bicyclol against pulmonary fibrosis via regulation of microRNA‐455‐3p in rats

“…Moreover, it is known that medicine eases or cures disease by influence of cellular protein synthesis, which is typically controlled by micro-RNAs (miRNAs). 12,13 In addition, bicyclol can potentially inhibit cell apoptosis and promote cell proliferation and differentiation via regulation of the related genes such as B-cell lymphoma factor 2 (Bcl-2) through multiple signaling pathways, thus exerting the biological effects of inhibiting apoptosis. 10 Furthermore, various miRNAs can modulate multiple pathways and genes, however changing miRNAs' expression may influence pathological processes of the lung, such as lung fibrosis or inflammatory diseases.…”

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

“…In case of co-treatment with RMP and INH, the issue is that RMP is a potent inducer of CYP2E1, which is the major enzyme responsible for metabolism of INH [126, 127]. Thus, at chronic therapeutic doses, the combination therapy results in increased production of the toxic acetylhydrazine and hydrazine metabolites in the liver.…”

“…Further evidence shows that the mitochondrial oxidative stress induces apoptotic cell death after RMP-INH treatment in mice [128], HepG2 cell and AHH1 cell lines [132, 138]. The concept that RMP-INH mediated apoptotic cell death of hepatocytes is mediated via mitochondrial cytochrome c release and mitochondrial mediated caspase activation is supported by a number of studies, which show that RMP-INH mediated mitochondrial ROS production inhibits Nrf2 function [140] and induces pro-caspase-8 & 10 activation in rats [126, 140]. Furthermore, altered mitochondria-mediated changes in Bcl-2/Bax content, mitochondrial release of cytochrome c and caspase activation were also all shown to be responsible for INH- induced mitochondria mediated apoptosis in HepG2 cells [132].…”