Adverse effects of anti-tuberculosis drugs on HepG2 cell bioenergetics

Abstract

<jats:p> Tuberculosis (TB) is an intractable chronic infection. Disease treatment with anti-TB drugs remains challenging due to drug-induced hepatotoxicity. The toxicity of the anti-TB drugs rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) either alone or in combination was investigated in HepG2 cells. Assays of intracellular adenosine triphosphate (ATP) levels at 4-, 24- and 48-h post-exposure to gradient concentrations of RIF, INH and PZA were conducted. Drug-induced effects on mitochondrial membrane potential (MMP), mitochondrial complex I and complex III activity, nicotinamide adenine dinucleotide (NAD<jats:sup>+</jats:sup>) levels and cellular lactate production were assessed. Decreased ATP levels were dose-dependent and correlated with drug exposure duration. Approximate 24-h IC<jats:sub>50</jats:sub>s were 0.5 mM, 70 mM and 84 mM for RIF, INH and PZA, respectively. Twenty-four hours post-drug treatment, reductions of MMP ( p = 0.0005), mitochondrial complex I and III activities ( p = 0.0001 and p = 0.0003, respectively), NAD<jats:sup>+</jats:sup> levels ( p = 0.0057) and increased lactate production ( p &lt; 0.0001) were observed. Drug combinations used to mimic cumulative drug treatments induced a synergistic inhibition of mitochondrial complex I activity. An assessment of cellular ultrastructure using transmission electron microscopy indicated drug-induced mitophagy. Collectively, our study suggests that hepatotoxicity of commonly employed anti-TB drugs is mediated by their curtailment of mitochondrial function. </jats:p>

AMPK Activation Prevents and Reverses Drug-Induced Mitochondrial and Hepatocyte Injury by Promoting Mitochondrial Fusion and Function

“…Anti-tuberculosis drugs (e.g. rifampicin, isoniazid) induce mitophagy in HepG2 cells [57], and clinical concentrations of efavirenz promote mitophagy [58]. In contrast, perfluorooctane sulfonate impaired mitophagy in HepG2 cells [59], and amitriptyline impaired mitophagy in human hepatocytes [60].…”

The Isoniazid Metabolites Hydrazine and Pyridoxal Isonicotinoyl Hydrazone Modulate Heme Biosynthesis

“…These previous studies have established the relation between the [2Fe-2S]-containing FECH and iron levels in murine erythroleukemia cells, macrophage cell line RAW 264.7, and K562 cells and have shown that FECH is downregulated in ironlimiting conditions and upregulated in iron-replete conditions. However, there have been reports of the relation between FECH and iron levels in the liver hepatoma cell line HepG2/C3A, which is commonly used to study hepatotoxicity in vitro and has been used to demonstrate the toxicity of rifampicin and isoniazid at millimolar concentrations (Elmorsy et al, 2017;Shih et al, 2013;Singh et al, 2011;Tostmann et al, 2008). Additionally, because the FBS added to cell culture medium contained iron at a concentration of 26 mM, the cell culture medium conditions required for iron-mediated rescue by exogenous iron administration had Figure 2.…”

Investigation of Hepatoprotective and Antioxidant Activity of Celosia argentea against Tissue Injury Caused by Rifampicin Administration

“…Rifampicin is a known inducer of many metabolizing enzymes; some metabolites produce through these reactions are toxic and their accumulation would result in the induction of liver injury or immune responses [31]. Rifampicin could also cause the accumulation of reactive oxygen species (ROS) as a result of mitochondrial toxicity [32]. The liver injury caused by chemicals or infectious agents if not treated may progress to liver fibrosis, cirrhosis and liver failure [7].…”