Adverse effects of anti-tuberculosis drugs on HepG2 cell bioenergetics

Elmorsy, E.; Attalla, S.M.; Fikry, E.; Kocon, A.; Turner, R.; Christie, D.; Warren, A.; Nwidu, Lucky Legbosi; Carter, Wayne

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.

Citation

Elmorsy, E., Attalla, S., Fikry, E., Kocon, A., Turner, R., Christie, D., Warren, A., Nwidu, L. L., & Carter, W. (in press). Adverse effects of anti-tuberculosis drugs on HepG2 cell bioenergetics. Human and Experimental Toxicology, https://doi.org/10.1177/0960327116660751

• Journal Article Type: Article
• Acceptance Date: May 11, 2016
• Online Publication Date: Jul 26, 2016
• Deposit Date: Dec 5, 2016
• Publicly Available Date: Dec 5, 2016
• Journal: Human and Experimental Toxicology
• Print ISSN: 0960-3271
• Electronic ISSN: 1477-0903
• Publisher: SAGE Publications
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1177/0960327116660751
• Keywords: anti-TB drugs, drug-induced hepatoxicity, mitachondrial complex I and complex III activity, mitochondrial membrane potential mitophany
• Public URL: https://nottingham-repository.worktribe.com/output/799385
• Publisher URL: http://journals.sagepub.com/doi/10.1177/0960327116660751
• Contract Date: Dec 5, 2016