A model of isoniazid-induced hepatotoxicity in rabbits

Sarich, Troy C.; Zhou, Ting; Adams, Stephen P.; Bain, Allen I.; Wall, Richard A.; Wright, James M

doi:10.1016/1056-8719(95)00044-i

Cited by 61 publications

(42 citation statements)

References 23 publications

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“…Progress in finding an exact mechanism for and establishing a suitable animal model of INH-induced hepatotoxicity has faced many obstacles (31). In accordance with this challenge, the present study aimed to prove our hypothesis that coexposure to INH and LPS intensifies INH-induced liver injury.…”

Section: Discussionsupporting

confidence: 50%

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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Section: Discussionsupporting

confidence: 50%

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 pattern of hepatotoxicity produced in rabbits resembles that of human. 8 In our study treatment was given orally, as oral route is the preferred route of administration of anti tubercular drugs. Monotherapy with antitubercular drugs can lead to rapid development of resistance resulting in multi drug resistance tuberculosis that is very difficult to treat.…”

Section: Discussionmentioning

confidence: 99%

Effect of and #945;-tocopherol on antitubercular drugs induced hepatotoxicity

et al. 2016

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“…The closest animal model was described by Sarich et al 36 Rabbits were treated with isoniazid at 3-hour intervals for 2 days. This treatment led to increased levels of transaminases that peaked at ~36 hours as well as focal areas of liver necrosis in some of the animals.…”

Section: Isoniazid-induced Hepatotoxicity In the Rabbitmentioning

confidence: 99%

Role of animal models in the study of drug-induced hypersensitivity reactions

Uetrecht

2005

AAPS J

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A BSTRACTDrug-induced hypersensitivity reactions (DHRs) are a major problem, in large part because of their unpredictable nature. If we understood the mechanisms of these reactions better, they might be predictable. Their unpredictable nature also makes mechanistic studies very diffi cult, especially prospective clinical studies. Animal models are vital to most biomedical research, and they are almost the only way to test basic hypotheses of DHRs, such as the involvement of reactive metabolites. However, useful animal models of DHRs are rare because DHRs are also unpredictable in animals. For example, sulfonamide-induced DHRs in large-breed dogs appear to be valid because they are very similar to the DHRs that occur in humans; however, the incidence is only ~0.25%, and large-breed dogs are diffi cult to use as an animal model. Two more practical models are penicillamine-induced autoimmunity in the Brown Norway rat and nevirapine-induced skin rash in rats. The toxicity in these models is clearly immune mediated. In other models, such as amodiaquineinduced agranulocytosis/hepatotoxicity and halothaneinduced hepatotoxicity, the drug induces an immune response but there is no clinical toxicity. This fi nding suggests that regulatory mechanisms usually limit toxicity. Many of the basic characteristics of the penicillamine and nevirapine models, such as memory and tolerance, are quite different suggesting that the mechanisms are also signifi cantly different. More animal models are needed to study the range of mechanisms involved in DHRs; without them, progress in understanding such reactions is likely to be slow. K EYWORDS: animal models , hypersensitivity reactions , idiosyncratic drug reactions , penicillamine , nevirapine , popliteal lymph node assay INTRODUCTIONTo an immunologist, the term hypersensitivity implies an immune-mediated reaction. The term drug-induced hypersensitivity reaction (DHR) is used to describe a syndrome consisting of fever, rash, and involvement of various organs associated with drugs such as phenytoin, carbamazepine, abacavir, sulfonamides, and allopurinol; however, it is also frequently used to describe any idiosyncratic drug reaction. For many of the adverse reactions to be discussed in this review, it has not been conclusively demonstrated that they are immune mediated, and the term hypersensitivity reaction will be used broadly to refer to any idiosyncratic drug reaction that has features that suggest it is immune mediated. Another working hypothesis for this review, which is supported by a large amount of circumstantial evidence, 1 but in virtually no case proven, is that most DHRs are caused by reactive metabolites. Therefore, a major role of animal models is to test whether reactive metabolites are responsible for hypersensitivity reactions and further to determine how reactive metabolites provoke an immune response.A major characteristic of DHRs is their unpredictable or idiosyncratic nature. This means that at the present time it is impossible to predict which drug candidates will...

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A model of isoniazid-induced hepatotoxicity in rabbits

Cited by 61 publications

References 23 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

Effect of and #945;-tocopherol on antitubercular drugs induced hepatotoxicity

Role of animal models in the study of drug-induced hypersensitivity reactions

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