Adverse effects of anti-tuberculosis drugs on HepG2 cell bioenergetics
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 cell...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Published: |
SAGE
2016
|
| Subjects: | |
| Online Access: | https://eprints.nottingham.ac.uk/39181/ |
| _version_ | 1848795782191251456 |
|---|---|
| author | Elmorsy, E. Attalla, S.M. Fikry, E. Kocon, A. Turner, R. Christie, D. Warren, A. Nwidu, Lucky Legbosi Carter, Wayne |
| author_facet | Elmorsy, E. Attalla, S.M. Fikry, E. Kocon, A. Turner, R. Christie, D. Warren, A. Nwidu, Lucky Legbosi Carter, Wayne |
| author_sort | Elmorsy, E. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T19:37:33Z |
| format | Article |
| id | nottingham-39181 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:37:33Z |
| publishDate | 2016 |
| publisher | SAGE |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-391812020-05-04T17:59:34Z https://eprints.nottingham.ac.uk/39181/ 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 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. SAGE 2016-07-26 Article PeerReviewed Elmorsy, E., Attalla, S.M., Fikry, E., Kocon, A., Turner, R., Christie, D., Warren, A., Nwidu, Lucky Legbosi and Carter, Wayne (2016) Adverse effects of anti-tuberculosis drugs on HepG2 cell bioenergetics. Human and Experimental Toxicology . ISSN 1477-0903 anti-TB drugs drug-induced hepatoxicity mitachondrial complex I and complex III activity mitochondrial membrane potential mitophany http://journals.sagepub.com/doi/10.1177/0960327116660751 doi:10.1177/0960327116660751 doi:10.1177/0960327116660751 |
| spellingShingle | anti-TB drugs drug-induced hepatoxicity mitachondrial complex I and complex III activity mitochondrial membrane potential mitophany Elmorsy, E. Attalla, S.M. Fikry, E. Kocon, A. Turner, R. Christie, D. Warren, A. Nwidu, Lucky Legbosi Carter, Wayne Adverse effects of anti-tuberculosis drugs on HepG2 cell bioenergetics |
| title | Adverse effects of anti-tuberculosis drugs on HepG2 cell
bioenergetics |
| title_full | Adverse effects of anti-tuberculosis drugs on HepG2 cell
bioenergetics |
| title_fullStr | Adverse effects of anti-tuberculosis drugs on HepG2 cell
bioenergetics |
| title_full_unstemmed | Adverse effects of anti-tuberculosis drugs on HepG2 cell
bioenergetics |
| title_short | Adverse effects of anti-tuberculosis drugs on HepG2 cell
bioenergetics |
| title_sort | adverse effects of anti-tuberculosis drugs on hepg2 cell
bioenergetics |
| topic | anti-TB drugs drug-induced hepatoxicity mitachondrial complex I and complex III activity mitochondrial membrane potential mitophany |
| url | https://eprints.nottingham.ac.uk/39181/ https://eprints.nottingham.ac.uk/39181/ https://eprints.nottingham.ac.uk/39181/ |