Changes in Gene Expression Induced by Carbamazepine and Phenytoin: Testing the Danger Hypothesis

Lu, Wei; Li, Xujian; Uetrecht, Jack

doi:10.1080/15476910802085723

Cited by 14 publications

(6 citation statements)

References 17 publications

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“…We have used microarray studies to search for evidence of danger signals generated by drugs that cause a relatively high incidence of IDRs. Although we and others have found changes in gene expression that could represent a danger signal, we have not observed any consistent patterns that could be used to screen drug candidates for the risk that they would cause IDRs [243][244][245][246]. Furthermore, it is very difficult to determine if the changes that were observed actually represent danger signals.…”

Section: Implications Of Reactive Metabolites For Specific Mechanisticontrasting

confidence: 68%

Idiosyncratic Drug Reactions and the Potential Role of Metabolism

Uetrecht¹

2012

Encyclopedia of Drug Metabolism and Interactions

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There is a large amount of circumstantial evidence that supports the hypothesis that most idiosyncratic drug reactions (IDRs) are caused by reactive metabolites rather than the parent drug. When the total daily dose is included in the calculation, there is a rough correlation between the amount of covalent binding and the risk that a drug will be associated with a significant incidence of IDRs, especially those affecting the liver. However, there are drugs that form a large amount of reactive metabolites and rarely cause IDRs, and there are drugs such as ximelagatran that do not appear to form reactive metabolites and yet had to be withdrawn from the market because of an unacceptable risk of IDRs. There are a wide variety of proteins that are targets of covalent binding, and clearly, not all covalent binding is associated with the same risk of causing an IDR. It is likely that most IDRs are immune mediated, although this is not without controversy, especially with respect to idiosyncratic liver toxicity. There are several hypotheses that address the issue of how drugs initiate an immune response, but in the absence of valid animal models, they are very difficult to rigorously test. These hypotheses include the hapten hypothesis, the danger hypothesis, the p‐I (pharmacological interaction) hypothesis, epigenetic effects leading to activation of the immune system, direct activation of antigen‐presenting cells, and some of the newer biological agents simply appear to alter the balance in the immune system and do not involve reactive metabolites. It is likely that the mechanism by which different drugs induce an immune response is different, at least in detail. There are also hypotheses that do not involve the immune system such as mitochondrial toxicity and the inflammagen hypothesis. In the absence of valid animal models, it is important to use the clinical characteristics of IDRs to evaluate the hypotheses. A very important characteristic is the usual delay between starting a drug and the onset of the IDR. Another important characteristic is that different drugs can cause different types of IDRs in different people and even the same drug can cause different types of IDRs in different people. This is most easily explained by an immune mechanism in which this variability is due to variability in T‐cell‐receptor specificity, which is different even in identical twins. However, until we have a much better understanding of the detailed mechanisms of IDRs, it will be difficult to predict which drug candidates are likely to cause a relatively high incidence of IDRs and which patients are at high risk of such adverse reactions.

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Section: Implications Of Reactive Metabolites For Specific Mechanisticontrasting

confidence: 68%

Idiosyncratic Drug Reactions and the Potential Role of Metabolism

Uetrecht¹

2012

Encyclopedia of Drug Metabolism and Interactions

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“…The genetic variants in ABCC2, EPHX1, TNF, and HSPA1L that affect susceptibility to CBZ can be used to predict maintenance doses of CBZ 21,23-25 . CBZ exerts an influence on genes related to the Keap1-Nrf2-ARE signaling pathway, enzymes involved in oxidative-stress response, glutathione transferase, and heat shock proteins 26 . According to the Comparative Toxicogenomics Database (CTD), CBZ will have an effect on lung neoplasm induced by disruption of CCND1, CYP2A6, ERBB2, ESR1, FOS, NOS2, and TNF expression.…”

Section: Discussionmentioning

confidence: 99%

Identification of genes induced by carbamazepine in human bronchial epithelial BEAS-2B cells

Song

Kim

Ryu

2011

Toxicol. Environ. Health Sci.

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Some drugs are limited in their clinical application due to their propensity for inducing adverse side effects. We examined some clinical chemotherapeutic agents that have pulmonary toxic effects. Carbamazepine (CBZ) is an antiepileptic agent and its long-term use is associated with interstitial pneumonia, pulmonary fibrosis, and pulmonary infiltration with eosinophilia. CBZ is persistent in the environment and is frequently detected in water systems. A new technique in toxicity screening, "toxicogenomic technology", represents a useful approach for evaluating the toxic properties of new drug candidates early in the drug discovery process and their potential effects on the environment. To this end, we have examined gene expression profiles in BEAS-2B cells (a human bronchial epithelial cell line) following exposure to CBZ, which induced pulmonary toxicity, by using a human oligonucleotide chip. We identified 518 up-and 496 down-regulated genes whose expression had changed by more than 1.5-fold ( p⁄0.01) following CBZ exposure. Gene Ontology (GO) analysis showed elevation in the expression of genes involved in several key biological processes related to pulmonary toxicity, such as cholesterol metabolism, cell proliferation, and cell cycle regulation. In conclusion, the present study indicates that CBZ exerts its toxicity by modulating mRNA expression in BEAS-2B cells. We suggest that genes expressed by CBZ might serve as a molecular signature, which could be used more widely when implemented in combination with more traditional techniques, for the assessment and prediction of toxicity following CBZ-exposure.

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“…Carbamazepine is a drug causing idiosyncratic reactions in patients that produces a strong OS/RM response yet is non-toxic at high dose (225 mg/kg) in rats [8,9]. Although some rats showed obvious hepatotoxicity (Figure 1) in response to combined low dose LPS + carbamazepine as expected, the response was quite variable, so the rats were divided into responders and non-responders (Table 3) to assess differences in gene expression.…”

Section: Low Dose Lps Modelmentioning

confidence: 99%

“…Many companies screen the reactivity of their compounds and metabolites by covalent binding and/or glutathione conjugations to avoid potential problems and to optimize lead selection [6,7]. Transcriptomics and toxicogenomics approaches have also been used, which give a functional readout of the reactive metabolites [8,9]. Nrf2 appears to be a critical transcription factor in protecting against the oxidative stress caused by many of the reactive metabolites [10].…”

Section: Introductionmentioning

confidence: 99%

Repression of oxidative stress/reactive metabolite regulated gene expression is associated with conversion of carbamazepine into a hepatotoxicant in LPS and DSS rat models

Leone¹,

Saleh²,

Proctor³

et al. 2014

ABB

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Idiosyncratic hepatotoxicity accounts for many drug failures in the clinic and is a leading cause for blackboxed and withdrawn drugs. This toxicity has proven difficult to predict preclinically, but correlates with oxidative stress/reactive metabolites (OS/RM). As noted previously for antiepileptic compounds, many drugs causing idiosyncratic adverse drug effects are detected by OS/RM gene expression responses in the rat. In the present study, two immune activation models, low dose lipopolysaccharide (1 mg/kg IV) and 5% dextran sulphate sodium (DSS) in drinking water, were examined to determine if either would convert the non-toxic idiosyncratic toxicant carbamazepine (225 mg/kg) into a rat hepatotoxicant at 24 hours. Using the low dose LPS model, about 1/3 of the carbamazepine-treated rats either showed robust ALT and AST elevations with histopathological evidence of hepatotoxicity, or died. Rats in this LPS/carbamazepine group were subdivided based on ALT values into non-responders, responders or robust responders. Whereas most carbamazepine-induced mRNAs were repressed by LPS across all rats in this group, the OS/ RM genes aflatoxin aldehyde reductase (Afar) and glutathione transferase Ya (Gstya) were repressed only in the robust responder subgroup; it is unclear whether repression of these genes contributes to or results from hepatotoxicity. The OS/RM gene microsomal epoxide hydrolase (mEphx) showed repression across all rats. NAD(P)H: menadione oxidoreductase (Nmor) is an OS/RM-responsive gene that is also induced by LPS, confounding interpretation of its changes. After pretreatment with 5% DSS at 24 hours or for 5 days, using a protocol that reportedly produces increased endotoxin absorption, carbamazepine was not converted to a hepatototoxicant in any rats. Instead, DSS produced a pronounced (2-to 6-fold) and selective potentiation of carbamazepine induction of OS/RM-responsive mRNAs. The lack of repressive effects of DSS on these mRNAs or in converting carbamazepine to a hepatotoxicant was not due to desensitization of endotoxin responses since LPS was at least as effective when administered to DSS-pretreated rats. OS/RM gene repression may contribute to development of hepatotoxicity of carbamazepine in immune activation models.

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Changes in Gene Expression Induced by Carbamazepine and Phenytoin: Testing the Danger Hypothesis

Cited by 14 publications

References 17 publications

Idiosyncratic Drug Reactions and the Potential Role of Metabolism

Idiosyncratic Drug Reactions and the Potential Role of Metabolism

Identification of genes induced by carbamazepine in human bronchial epithelial BEAS-2B cells

Repression of oxidative stress/reactive metabolite regulated gene expression is associated with conversion of carbamazepine into a hepatotoxicant in LPS and DSS rat models

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