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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

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Authors

E. Elmorsy

S.M. Attalla

E. Fikry

A. Kocon

R. Turner

D. Christie

A. Warren

Lucky Legbosi Nwidu



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., …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

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