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.

Quercetin protected against isoniazide‐induced HepG2 cell apoptosis by activating the SIRT1/ERK pathway

“…To date, apoptosis has been recognized as an important factor responsible for INH‐induced hepatotoxicity. A variety of vivo studies have demonstrated that INH toxicity results from the induction of apoptosis with associated disruption of mitochondrial membrane potential and DNA strand breaks . Recent reports suggested that INH induces oxidative stress, mitochondria dysfunction, and apoptosis in HepG2 cells .…”

Venlafaxine-Induced Cytotoxicity Towards Isolated Rat Hepatocytes Involves Oxidative Stress and Mitochondrial/Lysosomal Dysfunction

“…34,35 Liver Mitochondria Isolation The continual centrifugation technique was performed to isolate Sprague Dawley rats liver mitochondria. 36 The minced rat liver was suspended in an ice cold mannitol solution comprising 75 mM sucrose, 0.225 M Dmannitol and 0.2 mM EDTA and then was centrifuged at 1,000× g for 10 min at 4ºC to sieve the debris. Centrifugation was performed once more to yield a dark layer that was re-suspended in the mannitol solution and re-centrifuged twice at 10,000×g for 10 min.…”

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

“…While an acute overdose of anti-TB drugs leads to neurotoxicity, chronic therapeutic treatment is the most common cause of liver injury [112, 113]. While hepatotoxicity due to RMP and INH is well documented [110, 114, 115], there are not many studies detailing the mechanisms behind liver injury induced by these drugs. Many risk factors such as age, alcohol consumption, gender and underlying diseases such as hepatitis B and C or cirrhosis could make TB patients undergoing anti-TB treatment more susceptible to RMP and INH hepatotoxicity [116–118].…”

“…The INH reactive metabolite, hydrazine, was shown to directly inhibit the activity of solubilized complex II in mouse hepatocytes while causing mitochondrial oxidant stress [135]. This INH induced mitochondrial oxidative stress affects mitochondrial dynamics in various ways [136]: INH induced mitochondrial ROS and reduced the membrane potential in rat liver mitochondria [115]. This was similarly demonstrated in HepG2 cells in which INH not only reduced the membrane potential but also induced mitochondrial swelling [136] and led to changes in mitochondrial structure and its perinuclear localization [136, 137].…”

“…Changes in mitochondrial morphology, excessive ROS production and cytochrome c release were also reported [148]. An evaluation of the mechanisms of INH-induced mitochondrial toxicity using rat liver mitochondria showed significant glutathione oxidation, ATP depletion and lipid peroxidation [115]. A mouse study found that impairment of mitochondrial complex I amplifies mitochondrial dysfunction and precipitates INH-induced hepatocellular injury [135].…”