Assessment of hepatotoxic liabilities by transcript profiling

Ruepp, Stefan; Boess, Franziska; Suter, Laura; Vera, M.; Steiner, Guido; Steele, Thomas D.; Weiser, Thomas; Albertini, Silvio

doi:10.1016/j.taap.2005.05.008

Cited by 46 publications

(12 citation statements)

References 39 publications

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“…All metabolic pathways in a biological system must be defined as well as the gene expressions that produce changes in the metabolome [34]. Transcriptomics is the science of measuring the entire set of RNA molecules (mRNA, rRNA, tRNA, and non-coding RNA) produced in a cell or organism to determine the genes that are actively expressed at any given time [34,178]. Transcript profiling for a reaction to a particular drug can provide an early alert to the risk of toxicity and elucidate pathogenic mechanisms [178].…”

Section: Re-challengementioning

confidence: 99%

“…Genome-wide association studies will enhance the knowledge base about genetic factors and facilitate the identification of multiple low risk polymorphisms that work in synergy (epistasis) to influence the phenotype of the disease [150]. Metabonomic and transcriptomic methods promise to elucidate the metabolic pathways and their genetic associations [177,178].…”

Section: Prevention and Future Directionsmentioning

confidence: 99%

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Drug-Induced Autoimmune-Like Hepatitis

2011

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The clinical phenotype of classical autoimmune hepatitis can be mimicked by idiosyncratic drug-induced liver injury, and differentiation can be difficult. The goals of this review are to enumerate the major agents of drug-induced autoimmune-like hepatitis, describe the clinical findings and risk factors associated with it, detail the clinical tools by which to assess causality, discuss putative pathogenic mechanisms, and describe treatment and outcome. The frequency of drug-induced autoimmune-like hepatitis among patients with classical features of autoimmune hepatitis is 9%. Minocycline and nitrofurantoin are implicated in 90% of cases. Female predominance, acute onset, and absence of cirrhosis at presentation are important clinical manifestations. Genetic factors affecting phase I and phase II transformations of the drug, polymorphisms that protect against cellular oxidative stress, and human leukocyte antigens that modulate the immune response may be important pathogenic components. Clinical judgment is the mainstay of diagnosis as structured diagnostic methods for drug-induced liver injury are imperfect. The covalent binding of a reactive drug metabolite to a hepatocyte surface protein (commonly a phase I or phase II enzyme), formation of a neoantigen, activation of CD8 T lymphocytes with nonselective antigen receptors, and deficient immune regulatory mechanisms are the main bases for a transient loss of self-tolerance. Discontinuation of the offending drug is the essential treatment. Spontaneous improvement usually ensues within 1 month. Corticosteroid therapy is warranted for symptomatic severe disease, and it is almost invariably effective. Relapse after corticosteroid withdrawal probably does not occur, and its absence distinguishes drug-induced disease from classical autoimmune hepatitis.

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Section: Re-challengementioning

confidence: 99%

Section: Prevention and Future Directionsmentioning

confidence: 99%

Drug-Induced Autoimmune-Like Hepatitis

2011

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“…The value created from mining vast amounts of gene expression data has allowed the linking of gene expression changes with traditional measurements of pharmacological and toxicological activity. This connection of traditional and novel data provides context and meaning to the alterations in gene expression caused by a candidate drug or chemical (Amin et al, 2002;Bushel et al, 2002;Hamadeh et al, 2002aHamadeh et al, , 2002bSteiner et al, 2004;Fielden et al, 2005;Ruepp et al, 2005). Further, this database has been mined using rigorous, statistical approaches based on sophisticated classification algorithms and logistic regression producing a library of linear, robust binary classifiers (Ganter et al, 2005;Natsoulis et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

NSAID-Induced Acute Phase Response is Due to Increased Intestinal Permeability and Characterized by Early and Consistent Alterations in Hepatic Gene Expression

Tugendreich

Pearson

Sagartz³

et al. 2006

Toxicol Pathol

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Toxicogenomics using a reference database can provide a better understanding and prediction of toxicity, largely by creating biomarkers that tie gene expression to actual pathology events. During the course of building a toxicogenomic database, an observation was made that a number of non-steroidal anti-inflammatory compounds (NSAIDs) at supra-pharmacologic doses induced an acute phase response (APR) and displayed hepatic gene expression patterns similar to that of intravenous lipopolysaccharide (LPS). Since NSAIDs are known to cause injury along the gastrointestinal tract, it has been suggested that NSAIDs increase intestinal permeability, allowing LPS and/or bacteria into the systemic circulation and stimulating an APR detectable in the liver. A short term study was subsequently conducted examining the effects of aspirin, indomethacin, ibuprofen, and rofecoxib to rats and a variety of endpoints were examined that included serum levels of inflammatory cytokines, histologic evaluation, and hepatic gene expression. Both indomethacin and ibuprofen injured the gastrointestinal tract, induced an APR, and increased serum levels of LPS, while rofecoxib and aspirin did not affect the GI tract or induce an APR. In treatments that eventually showed a systemic inflammatory response, hepatic expression of many inflammatory genes was noted as early as 6 hours after treatment well before alterations in traditional clinical pathology markers were detected. This finding led to the creation of a hepatic gene expression biomarker of APR that was effectively shown to be an early identifier of imminent inflammatory injury. In terms of the relative gastrointestinal safety and the NSAIDs studied, an important safety distinction can be made between the presumptive efficacious dose and the APR-inducing dose for indomethacin (1-2-fold), ibuprofen (5-fold), and rofecoxib (∼250-fold). Our data support the notion that NSAID-induced intestinal injury results in leakage of commensural bacteria and/or LPS into the circulation, provoking a systemic inflammatory response and that hepatic gene expression-based biomarkers can be used as early and sensitive biomarkers of APR onset.[The table referenced in this paper is not printed in this issue of Toxicologic Pathology. It is available as a downloadable text file in the online edition of Toxicologic Pathology, 34(2). In order to access the full article online, you must have either an individual subscription or a member subscription accessed through www.toxpath.org.]

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“…Hepatocytes were isolated from 10-to 14-week-old male HanBrl:WIST rats by a two-step collagenase liver perfusion method as previously described [9]. Briefly, the rats were anaesthetized with sodium pentobarbital (120 mg/kg, i.p.).…”

Section: Hepatocyte Preparation Culture and Treatmentmentioning

confidence: 99%

Gene expression‐based in vivo and in vitro prediction of liver toxicity allows compound selection at an early stage of drug development

Roth

Boess

Landes

et al. 2010

J Biochem & Molecular Tox

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We have analyzed gene expression and histopathology of rat liver treated with a histamine-3 receptor inverse agonist under development for the treatment of obesity 24 h after a single acute administration. While histopathology did not identify a clear liver toxicity, analysis of gene changes strongly suggested the development of toxicity. This prediction was confirmed in a 2-week repeat-dose rat study where prominent liver pathology occurred, while gene changes that lead to the prediction persisted. A subset of these genes was analyzed in vitro in both rat and human hepatocytes to reveal the potential relevancy of the findings for the situation in humans. This comprehensive analysis of the development compound at the gene expression level allowed interpretation of findings of the follow-up compound in a frontloaded 24-h single-dose acute study that was initiated before regular 2-week repeat-dose studies started. The high similarity of the follow-up compound to the lead compound based on gene expression lead to the immediate termination of the development program for this compound series. Our data demonstrate the value of genomics-based early toxicity prediction in short-term in vivo studies for the characterization of compounds to allow prioritization and selection of suited candidates before compound-, animal-, and cost-intensive longer term studies are undertaken.

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Assessment of hepatotoxic liabilities by transcript profiling

Cited by 46 publications

References 39 publications

Drug-Induced Autoimmune-Like Hepatitis

Drug-Induced Autoimmune-Like Hepatitis

NSAID-Induced Acute Phase Response is Due to Increased Intestinal Permeability and Characterized by Early and Consistent Alterations in Hepatic Gene Expression

Gene expression‐based in vivo and in vitro prediction of liver toxicity allows compound selection at an early stage of drug development

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