Adverse effects of anti-tuberculosis drugs on HepG2 cell bioenergetics

Elmorsy, E. and Attalla, S.M. and Fikry, E. and Kocon, A. and Turner, R. and Christie, D. and Warren, A. and Nwidu, L.L. and Carter, Wayne G. (2016) Adverse effects of anti-tuberculosis drugs on HepG2 cell bioenergetics. Human and Experimental Toxicology . ISSN 1477-0903

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Abstract

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+) levels and cellular lactate production were assessed. Decreased ATP levels were dose-dependent and correlated with drug exposure duration. Approximate 24-h IC50s 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+ levels (p = 0.0057) and increased lactate production (p < 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.

Item Type: Article
Keywords: anti-TB drugs, drug-induced hepatoxicity, mitachondrial complex I and complex III activity, mitochondrial membrane potential mitophany
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine
University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
Identification Number: https://doi.org/10.1177/0960327116660751
Depositing User: Eprints, Support
Date Deposited: 05 Dec 2016 15:46
Last Modified: 06 Dec 2016 23:31
URI: http://eprints.nottingham.ac.uk/id/eprint/39181

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