Assessment of reactive metabolites in drug-induced liver injury

Lee, Kye Sook; Oh, Soo Jin; Kim, Hwan Mook; Lee, Kiho; Kim, Sang Kyum

doi:10.1007/s12272-011-1108-x

Cited by 12 publications

(7 citation statements)

References 30 publications

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“…For example, toxicant-induced changes in mitochondria permeability are usually injuries that cause cell death but there are occasions that a cell can go through lysosomal autophagy limiting the injury and promoting survival [55] . These phenomena can be explained by self-protection of an organism, where reactive metabolites or parent compounds can be deactivated through conjugation to glutathione, which protects a cell from oxidative stress [56,57] . Glutathione can also bind to proteins in a process named as “glutathionylation”, which potentially can protect them from additional damage due to toxicant binding to cysteine groups in the proteins [57,58] .…”

Section: Resultsmentioning

confidence: 99%

“…These phenomena can be explained by self-protection of an organism, where reactive metabolites or parent compounds can be deactivated through conjugation to glutathione, which protects a cell from oxidative stress [56,57] . Glutathione can also bind to proteins in a process named as “glutathionylation”, which potentially can protect them from additional damage due to toxicant binding to cysteine groups in the proteins [57,58] . The cell can also protect itself from DNA adducts by removing the modified DNA from the biosystem [59] .…”

Section: Resultsmentioning

confidence: 99%

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Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity

Sun¹,

Slavov²,

Schnackenberg³

et al. 2014

Computational and Structural Biotechnology Journal

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It has been estimated that 10% of acute liver failure is due to “idiosyncratic hepatotoxicity”. The inability to identify such compounds with classical preclinical markers of hepatotoxicity has driven the need to discover a mechanism-based biomarker panel for hepatotoxicity. Seven compounds were included in this study: two overt hepatotoxicants (acetaminophen and carbon tetrachloride), two idiosyncratic hepatotoxicants (felbamate and dantrolene), and three non-hepatotoxicants (meloxicam, penicillin and metformin). Male Sprague–Dawley rats were orally gavaged with a single dose of vehicle, low dose or high dose of the compounds. At 6 h and 24 h post-dosing, blood was collected for metabolomics and clinical chemistry analyses, while organs were collected for histopathology analysis. Forty-one metabolites from previous hepatotoxicity studies were semi-quantified and were used to build models to predict hepatotoxicity. The selected metabolites were involved in various pathways, which have been noted to be linked to the underlying mechanisms of hepatotoxicity. PLS models based on all 41 metabolite or smaller subsets of 6 (6 h), 7 (24 h) and 20 (6 h and 24 h) metabolites resulted in models with an accuracy of at least 97.4% for the hold-out test set and 100% for training sets. When applied to the external test sets, the PLS models predicted that 1 of 9 rats at both 6 h and 24 h treated with idiosyncratic liver toxicants was exposed to a hepatotoxic chemical. In conclusion, the biomarker panel might provide information that along with other endpoint data (e.g., transcriptomics and proteomics) may diagnose acute and idiosyncratic hepatotoxicity in a clinical setting.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity

Sun¹,

Slavov²,

Schnackenberg³

et al. 2014

Computational and Structural Biotechnology Journal

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show abstract

“…Druginduced liver injury (DILI), in particular, is a major problem since these incidences in many cases cause severe hepatic injury, are difficult to predict, and often are identified only after marketing of the drug. In fact, DILI is one of the most frequent reasons for the withdrawal of an approved drug from the market, and accounts for up to 50% of acute liver failure cases [1,2]. DILI is also one of the most common reasons that clinical trials of new therapeutic agents are terminated.…”

Section: Introductionmentioning

confidence: 99%

Hepatic Differentiation and Maturation of Human Embryonic Stem Cells Cultured in a Perfused Three-Dimensional Bioreactor

Sivertsson

Synnergren

Jensen³

et al. 2013

Stem Cells and Development

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Drug-induced liver injury is a serious and frequently occurring adverse drug reaction in the clinics and is hard to predict during preclinical studies. Today, primary hepatocytes are the most frequently used cell model for drug discovery and prediction of toxicity. However, their use is marred by high donor variability regarding drug metabolism and toxicity, and instable expression levels of liver-specific genes such as cytochromes P450. An in vitro model system based on human embryonic stem cells (hESC), with their unique properties of pluripotency and self-renewal, has potential to provide a stable and unlimited supply of human hepatocytes. Much effort has been made to direct hESC toward the hepatic lineage, mostly using 2-dimensional (2D) cultures. Although the results are encouraging, these cells lack important functionality. Here, we investigate if hepatic differentiation of hESC can be improved by using a 3-dimensional (3D) bioreactor system. Human ESCs were differentiated toward the hepatic lineage using the same cells in either the 3D or 2D system. A global transcriptional analysis identified important differences between the 2 differentiation regimes, and we identified 10 pathways, highly related to liver functions, which were significantly upregulated in cells differentiated in the bioreactor compared to 2D control cultures. The enhanced hepatic differentiation observed in the bioreactor system was also supported by immunocytochemistry. Taken together, our results suggest that hepatic differentiation of hESC is improved when using this 3D bioreactor technology as compared to 2D culture systems.

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“…Cell culture media was purchased from Invitrogen (Carlsbad, CA), [1,[2][3] H]-cortisone from American Radiolabeled Chemicals (St.Louis, MO), and all other chemicals were from Fluka AG (Buchs, Switzerland).…”

Section: Methodsmentioning

confidence: 99%

“…Drug-Induced Liver Injury (DILI) is the major severe adverse drug reaction of marketed drugs, with severe health consequences for the patients and financial loss for the pharmaceutical industry due to market withdrawal [1]. For the evaluation of safety profiles for novel drug candidates and the prediction of adverse drug effects, improved in vitro liver models are of great demand.…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Rat Multi-Cell Type 3D-Liver Microtissue System

Odermatt¹

2013

J Tissue Sci Eng

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Background: Primary hepatocytes rapidly lose their polarized morphology and the expression of important liverspecific metabolic enzymes, receptors and transport proteins under normal two-dimensional (2D) culture conditions. Thus, their use as a reliable predictive in vitro model for drug-induced liver injury is limited. Three-dimensional (3D) liver micro tissue culture systems have become an increasingly attractive alternative for the evaluation of druginduced liver toxicity. However, several liver-specific pathways remain to be characterized in such models. Methods and principal findings:In the present work, we compared the expression of several genes with a role in the anti-oxidant cell defense and glucocorticoid pathways in rat H4IIE hepatoma cells, primary rat hepatocytes, 2D-hepatocyte sandwich culture, and a multi-cell type micro tissue model comprising primary rat hepatocytes in coculture with liver-derived nonparenchymal cells and macrophage (Kupffer cells). Gene expression was studied for up to 25 days in culture. High expression levels of the Nrf2-dependent genes NQO1, ABCC3 and GST2A were detected in H4IIE cells and in 3D-liver microtissues, in contrast to 2D-hepatocytes where a rapid decline of these genes was observed. The glucocorticoid-dependent genes ORM1, G6PC, PCK1 and HSD11B1 were highly expressed up to 25 days of cultivation in 3D-liver microtissues, but they showed very low or background expression in H4IIE and 2D-hepatocyte models. Conclusions:The tested 3D-multi-cell type liver micro tissue represents a stable and functionally active model system, with sustained expression for more than three weeks of cultivation of important metabolic proteins regulated by the glucocorticoid and anti-oxidant cell defense pathway.

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Assessment of reactive metabolites in drug-induced liver injury

Cited by 12 publications

References 30 publications

Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity

Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity

Hepatic Differentiation and Maturation of Human Embryonic Stem Cells Cultured in a Perfused Three-Dimensional Bioreactor

Characterization of a Rat Multi-Cell Type 3D-Liver Microtissue System

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