title: Mitochondrial oxidative stress and dysfunction induced by isoniazid: study on isolated rat liver and brain mitochondria.
abstract: Isoniazid (INH or isonicotinic hydrazide) is used for the treatment and prophylaxis of tuberculosis. Liver and brain are two important target organs in INH toxicity. However, the exact mechanisms behind the INH hepatotoxicity or neurotoxicity have not yet been completely understood. Considering the mitochondria as one of the possible molecular targets for INH toxicity, the aim of this study was to evaluate the mechanisms of INH mitochondrial toxicity on isolated mitochondria. Mitochondria were isolated by differential ultracentrifugation from male Sprague-Dawley rats and incubated with different concentrations of INH (25-2000 μM) for the investigation of mitochondrial parameters. The results indicated that INH could interact with mitochondrial respiratory chain and inhibit its activity. Our results showed an elevation in mitochondrial reactive oxygen species (ROS) formation, lipid peroxidation and mitochondrial membrane potential collapse after exposure of isolated liver mitochondria in INH. However, different results were obtained in brain mitochondria. Noteworthy, significant glutathione oxidation, adenosine triphosphate (ATP) depletion and lipid peroxidation were observed in higher concentration of INH, as compared to liver mitochondria. In conclusion, our results suggest that INH may initiate its toxicity in liver mitochondria through interaction with electron transfer chain, lipid peroxidation, mitochondrial membrane potential decline and cytochrome c expulsion which ultimately lead to cell death signaling.
authors.affiliation: a Zanjan Applied Pharmacology Research Center, Zanjan University of Medical Sciences , Zanjan , Iran .|b Department of Pharmacology and Toxicology , School of Pharmacy, Zanjan University of Medical Sciences , Zanjan , Iran , and.
authors.forename: Morteza
authors.initials: M
authors.lastname: Ahadpour
authors.affiliation: b Department of Pharmacology and Toxicology , School of Pharmacy, Zanjan University of Medical Sciences , Zanjan , Iran , and.
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Eskandari
authors.affiliation: a Zanjan Applied Pharmacology Research Center, Zanjan University of Medical Sciences , Zanjan , Iran .
authors.forename: Vida
authors.initials: V
authors.lastname: Mashayekhi
authors.affiliation: a Zanjan Applied Pharmacology Research Center, Zanjan University of Medical Sciences , Zanjan , Iran .
authors.forename: Kamaleddin
authors.initials: K
authors.lastname: Haj Mohammad Ebrahim Tehrani
authors.affiliation: b Department of Pharmacology and Toxicology , School of Pharmacy, Zanjan University of Medical Sciences , Zanjan , Iran , and.
authors.forename: Iman
authors.initials: I
authors.lastname: Jafarian
authors.affiliation: c Faculty of Pharmacy , Shahid Beheshti University of Medical Sciences , Tehran , Iran.
authors.forename: Parvaneh
authors.initials: P
authors.lastname: Naserzadeh
authors.affiliation: a Zanjan Applied Pharmacology Research Center, Zanjan University of Medical Sciences , Zanjan , Iran .|b Department of Pharmacology and Toxicology , School of Pharmacy, Zanjan University of Medical Sciences , Zanjan , Iran , and.
authors.forename: Mir-Jamal
authors.initials: MJ
authors.lastname: Hosseini
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000633:toxicity*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007538:Isoniazid / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000995:Antitubercular Agents; D017382:Reactive Oxygen Species; D007538:Isoniazid
keywords: Isoniazid (INH); isolated mitochondria; mechanistic toxicity