Isoniazid-induced apoptosis in HepG2 cells: Generation of oxidative stress and Bcl-2 down-regulation

Bhadauria, Smrati; Mishra, Rajeev; Kanchan, Ranjana; Tripathi, Chakrapani; Srivastava, Anuradha; Tiwari, Ashutosh; Sharma, Sharad

doi:10.3109/15376511003793325

Cited by 37 publications

(26 citation statements)

References 31 publications

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“…soniazid (INH), since its introduction in the year 1952, still serves as a frontline drug in tuberculosis treatment (1). Despite the fact that INH has been widely used as a first-line antitubercular agent (2,3), its therapeutic value is usually accompanied by severe hepatotoxicity and lethal hepatic injury (4,5).…”

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confidence: 99%

Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment

Hassan

Guo

Yousef

et al. 2016

Antimicrob Agents Chemother

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Isoniazid (INH), since its introduction in the year 1952, still serves as a frontline drug in tuberculosis treatment (1). Despite the fact that INH has been widely used as a first-line antitubercular agent (2, 3), its therapeutic value is usually accompanied by severe hepatotoxicity and lethal hepatic injury (4, 5). Although the pathophysiology of INH-induced liver injury might vary, the toxicity features of the drug, including hepatocellular steatosis, necrosis, and inflammatory infiltration, are nearly consistent (6, 7).Even though extensive studies expounding INH toxicity have been carried out, the exact mechanism of INH hepatotoxicity remains controversial. Among numerous established theories, an inflammatory stress theory has recently been widely used to explain the idiosyncrasy. One hypothesis is that inflammatory stress increases sensitivity to drug-induced liver injury (DILI) (8, 9). In this theory, an incidence of systemic inflammation might reduce the xenobiotic toxicity threshold, which could be easily accomplished by coadministration with an inflammatory agent (10), thus promoting drug toxicity. Lipopolysaccharide (LPS) is an outer cell wall membrane constituent of Gram-negative bacteria that has been comprehensively studied as an inflammatory agent with a major role in bacterial infections (11,12). Previous studies have suggested that LPS might intensify DILI (13-15), and, hence, a possible cornerstone role for LPS in INH-induced hepatotoxicity might be assumed.Oxidative stress, generated from the accumulation of reactive oxygen species (ROS), may be potentiated by different factors, including drugs and inflammation (16,17). In addition, oxidative stress plays a major role in several types of hepatic injury (18). Furthermore, with cytochrome P450 2E1 (CYP2E1) playing a major role in drug metabolism and the pathophysiology of DILI (19) and being considered a principal element in human susceptibility to chemical toxins (20), it plays a central part in oxidative stress, production of ROS, and hepatotoxic injury. Moreover, a previous report proposed that hepatic CYP2E1 plays a fundamental role in the propagation of INH-induced hepatotoxicity, mainly throughout ROS generation (21). Nevertheless, a full understanding of CYP2E1 as a major hepatotoxin-forming, catalyzing enzyme and its influence on INH-induced liver damage has not been completely achieved.Studies of the hepatotoxic mechanisms of INH were previously conducted using different animal models; however, results were accompanied by the absence of certain features of INH toxicity, i.e., delayed onset or inconsistency in severity compared to that in hu-

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confidence: 99%

Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment

Hassan

Guo

Yousef

et al. 2016

Antimicrob Agents Chemother

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“…The decreased activities of SOD and CAT observed in INH treated mice was probably due to the interaction of the accumulated free radicals with the associated metal ions or with the active amino acids of these enzymes. During hepatotoxicity these enzymes are structurally and functionally impaired by free radical resulting in liver damage [14]. Our results showed that after administration of INH in combination with SH11 the levels of MDA (Figure 6) were decreased and the activities of the antioxidant enzymes SOD (Figure 7) and CAT (Figure 8) were amended.…”

Section: Discussionmentioning

confidence: 57%

Schiff base SH11 with tuberculostatic and radical scavenging activities against INH-induced oxidative hepatic damage

Georgieva

Yaneva²,

Nikolova³

2012

ABB

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“…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]. 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].…”

Section: Rifampin and Isoniazid Hepatotoxicitymentioning

confidence: 96%

“…In HepG2 cells, INH metabolites also cause manganese superoxide dismutase [127, 131], catalase, and glucose-6-phosphate dehydrogenase modifications [132]. These altered antioxidant functions lead to the loss of hepatocyte ability to efficiently detoxify acetylhydrazine and hydrazine.…”

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%

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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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Isoniazid-induced apoptosis in HepG2 cells: Generation of oxidative stress and Bcl-2 down-regulation

Cited by 37 publications

References 31 publications

Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment

Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment

Schiff base SH11 with tuberculostatic and radical scavenging activities against INH-induced oxidative hepatic damage

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

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