Mitochondrial oxidative stress and permeability transition in Isoniazid and Rifampicin induced liver injury in mice

Chowdhury, Abhijit; Santra, Amal; Bhattacharjee, Kanta; Ghatak, Subhadip; Saha, Dhira Rani; Dhali, Gopal Krishna

doi:10.1016/j.jhep.2006.01.027

Cited by 154 publications

(116 citation statements)

References 42 publications

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“…INH induced hepatotoxicity studies in both rats and humans reveal that there is a robust connection between isoniazid INH metabolic activation by CYP2E1, and ROS production and mitochondrial dysfunction [119, 133]. This is also consistent with data from RMP-INH co-treatment, showing that the drugs increase hepatic oxidant stress and trigger onset of the MPT [128]. 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].…”

Section: Rifampin and Isoniazid Hepatotoxicitysupporting

confidence: 60%

“…Thus, at chronic therapeutic doses, the combination therapy results in increased production of the toxic acetylhydrazine and hydrazine metabolites in the liver. This increase in toxic RMP-INH metabolites has been shown to affect cellular homeostasis by decreasing hepatic GSH in mice [128], and reducing mitochondrial ATP production [128]. Significant liver damage due to synergistic action of RMP-INH can be prevented by early detection of hepatic injury and NAC treatment [129].…”

Section: Rifampin and Isoniazid Hepatotoxicitymentioning

confidence: 99%

“…These altered antioxidant functions lead to the loss of hepatocyte ability to efficiently detoxify acetylhydrazine and hydrazine. As a result, acetylhydrazine and hydrazine bind covalently with hepatic mitochondrial proteins and inhibit their function [119, 128, 133] while decreasing ATP production and nicotinamide adenine dinucleotide levels [134]. INH induced hepatotoxicity studies in both rats and humans reveal that there is a robust connection between isoniazid INH metabolic activation by CYP2E1, and ROS production and mitochondrial dysfunction [119, 133].…”

Section: Rifampin and Isoniazid Hepatotoxicitymentioning

confidence: 99%

“…Decrease of DRP1 expression by INH was shown to be tightly linked with mitochondria mediated onset of apoptosis [136]. Further evidence shows that the mitochondrial oxidative stress induces apoptotic cell death after RMP-INH treatment in mice [128], HepG2 cell and AHH1 cell lines [132, 138]. The concept that RMP-INH mediated apoptotic cell death of hepatocytes is mediated via mitochondrial cytochrome c release and mitochondrial mediated caspase activation is supported by a number of studies, which show that RMP-INH mediated mitochondrial ROS production inhibits Nrf2 function [140] and induces pro-caspase-8 & 10 activation in rats [126, 140].…”

Section: Rifampin and Isoniazid Hepatotoxicitymentioning

confidence: 99%

“…Furthermore, altered mitochondria-mediated changes in Bcl-2/Bax content, mitochondrial release of cytochrome c and caspase activation were also all shown to be responsible for INH- induced mitochondria mediated apoptosis in HepG2 cells [132]. Detection of cytochrome c protein in the cytosol of mouse hepatocytes treated with RMP-INH also revealed its leakage from mitochondria [128]. All of these studies support a RMP-INH mediated mitochondrial mode of apoptotic cell death.…”

Section: Rifampin and Isoniazid Hepatotoxicitymentioning

confidence: 99%

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

et al. 2018

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Mitochondria are critical cellular organelles for energy generation and are now also recognized as playing important roles in cellular signaling. Their central role in energy metabolism, as well as their high abundance in hepatocytes, make them important targets for drug-induced hepatotoxicity. This review summarizes the current mechanistic understanding of the role of mitochondria in drug-induced hepatotoxicity caused by acetaminophen, diclofenac, anti-tuberculosis drugs such as rifampin and isoniazid, anti-epileptic drugs such as valproic acid and constituents of herbal supplements such as pyrrolizidine alkaloids. The utilization of circulating mitochondrial-specific biomarkers in understanding mechanisms of toxicity in humans will also be examined. In summary, it is well-established that mitochondria are central to acetaminophen-induced cell death. However, the most promising areas for clinically useful therapeutic interventions after acetaminophen toxicity may involve the promotion of adaptive responses and repair processes including mitophagy and mitochondrial biogenesis, In contrast, the limited understanding of the role of mitochondria in various aspects of hepatotoxicity by most other drugs and herbs requires more detailed mechanistic investigations in both animals and humans. Development of clinically relevant animal models and more translational studies using mechanistic biomarkers are critical for progress in this area.

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Section: Rifampin and Isoniazid Hepatotoxicitysupporting

confidence: 60%

Section: Rifampin and Isoniazid Hepatotoxicitymentioning

confidence: 99%

Section: Rifampin and Isoniazid Hepatotoxicitymentioning

confidence: 99%

Section: Rifampin and Isoniazid Hepatotoxicitymentioning

confidence: 99%

Section: Rifampin and Isoniazid Hepatotoxicitymentioning

confidence: 99%

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

et al. 2018

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Liver Toxicology

McGill¹,

Williams²,

Jaeschke³

2015

Mammalian Toxicology

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Effects of isatin‐isoniazid derivatives on drug metabolizing and chemoprotective enzymes in mice

El‐Sayed

Aboul‐Fadl

Franklin

2010

Drug Development Research

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Four isatin-isoniazid derivatives with proven efficacy against resistant strains of Mycobacterium tuberculosis, that had greater lipophilicity than isoniazid were evaluated for effects on hepatic drug metabolizing and chemoprotective enzymes and compared to isoniazid. Following intragastric administration to mice (75 or 150 mg/kg Â 3 days), none of the four compounds exhibited hepatotoxicity, and only isoniazid was found to elevate CYP2E1 activity. All compounds slightly elevated Cyp1a1/2 mRNA levels, but these did not result in increased methoxyresorufin demethylase activity. With the exception of isoniazid, approximately twofold elevations in Ugt1a mRNAs (seen with isatin-isoniazid [Ugt1a1, Ugt1a6, Ugt1a9], 1-propynylisatin-isoniazid [Ugt1a1, Ugt1a9], and 1-propylisatin-isoniazid [Ugt1a1]) also did not result in changes in 4-nitrophenol glucuronidation activity. 1-Benzylisatin-isoniazid was the only compound that (1) elevated Ugt2b5 mRNA, and (2) like isoniazid, had no effect on glutathione transferase activities and mRNAs. 1-Propynylisatin-isoniazid elevated glutathione transferase activity toward 1-chloro-2,4-dinitrobenzene, 1-propylisatin-isoniazid decreased the 2.4-kb Gstp transcript, and isatin-isoniazid increased Gsta, Gstm, and the 1.2-kb Gstp transcripts. None of the four compounds affected glutathione peroxidase activity, although 1-propynylisatin-isoniazid and 1-benzylisatin-isoniazid elevated mRNA transcripts. None of the four compounds affected microsomal epoxide hydrolase or thioredoxin reductase activities but, in parallel, isoniazid, 1-propynylisatin-isoniazid, and 1-propylisatin-isoniazid elevated mRNAs of each. 1-Propynylisatin-isoniazid, 1-propylisatin-isoniazid, and 1-benzylisatin-isoniazid, and isoniazid, elevated quinone oxidoreductase (Nqo1) mRNA, but only 1-propylisatin-isoniazid elevated the activity. Altogether, and despite some changes in mRNA expression, the novel isatin-isoniazid derivatives had only minor effects on mouse hepatic enzyme activities and are worthy of further investigation as possible therapeutic agents likely free of major induction-related drug-drug interactions. Drug Dev Res 71:313-322, 2010.

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Mitochondrial oxidative stress and permeability transition in Isoniazid and Rifampicin induced liver injury in mice

Cited by 154 publications

References 42 publications

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

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

Liver Toxicology

Effects of isatin‐isoniazid derivatives on drug metabolizing and chemoprotective enzymes in mice

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