Analysis of cell death inducing compounds

Publication: Research - peer-reviewJournal article – Annual report year: 2007

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Analysis of cell death inducing compounds. / Spicker, Jeppe; Pedersen, Henrik Toft; Nielsen, Henrik Bjørn; Brunak, Søren.

In: Archives of Toxicology, Vol. 81, No. 11, 2007, p. 803-811.

Publication: Research - peer-reviewJournal article – Annual report year: 2007

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Author

Spicker, Jeppe; Pedersen, Henrik Toft; Nielsen, Henrik Bjørn; Brunak, Søren / Analysis of cell death inducing compounds.

In: Archives of Toxicology, Vol. 81, No. 11, 2007, p. 803-811.

Publication: Research - peer-reviewJournal article – Annual report year: 2007

Bibtex

@article{5492bb5a06674af49ed9c20512935522,
title = "Analysis of cell death inducing compounds",
publisher = "Springer",
author = "Jeppe Spicker and Pedersen, {Henrik Toft} and Nielsen, {Henrik Bjørn} and Søren Brunak",
year = "2007",
doi = "10.1007/s00204-007-0207-4",
volume = "81",
number = "11",
pages = "803--811",
journal = "Archives of Toxicology",
issn = "0340-5761",

}

RIS

TY - JOUR

T1 - Analysis of cell death inducing compounds

A1 - Spicker,Jeppe

A1 - Pedersen,Henrik Toft

A1 - Nielsen,Henrik Bjørn

A1 - Brunak,Søren

AU - Spicker,Jeppe

AU - Pedersen,Henrik Toft

AU - Nielsen,Henrik Bjørn

AU - Brunak,Søren

PB - Springer

PY - 2007

Y1 - 2007

N2 - Biomarkers for early detection of toxicity hold the promise of improving the failure rates in drug development. In the present study, gene expression levels were measured using full-genome RAE230 version 2 Affymetrix GeneChips on rat liver tissue 48 h after administration of six different compounds, three toxins (ANIT, DMN and NMF) and three non-toxins (Caeruelein, Dinitrophenol and Rosiglitazone). We identified three gene transcripts with exceptional predictive performance towards liver toxicity and/or changes in histopathology. The three genes were: glucokinase regulatory protein (GCKR), ornithine aminotransferase (OAT) and Cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase) (Cyp2C29). RT-PCR for these three genes was performed and four additional compounds were included for validation. The quantitative RT-PCR analysis confirmed the findings based on the microarray data and using the three genes a classification rate of 55 of 57 samples was achieved for the classification of not toxic versus toxic. The single most promising biomarker (OAT) alone resulted in a surprisingly 100% correctly classified samples. OAT has not previously been linked to toxicity and cell death in the literature and the novel finding represents a putative hepatotoxicity biomarker.

AB - Biomarkers for early detection of toxicity hold the promise of improving the failure rates in drug development. In the present study, gene expression levels were measured using full-genome RAE230 version 2 Affymetrix GeneChips on rat liver tissue 48 h after administration of six different compounds, three toxins (ANIT, DMN and NMF) and three non-toxins (Caeruelein, Dinitrophenol and Rosiglitazone). We identified three gene transcripts with exceptional predictive performance towards liver toxicity and/or changes in histopathology. The three genes were: glucokinase regulatory protein (GCKR), ornithine aminotransferase (OAT) and Cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase) (Cyp2C29). RT-PCR for these three genes was performed and four additional compounds were included for validation. The quantitative RT-PCR analysis confirmed the findings based on the microarray data and using the three genes a classification rate of 55 of 57 samples was achieved for the classification of not toxic versus toxic. The single most promising biomarker (OAT) alone resulted in a surprisingly 100% correctly classified samples. OAT has not previously been linked to toxicity and cell death in the literature and the novel finding represents a putative hepatotoxicity biomarker.

U2 - 10.1007/s00204-007-0207-4

DO - 10.1007/s00204-007-0207-4

JO - Archives of Toxicology

JF - Archives of Toxicology

SN - 0340-5761

IS - 11

VL - 81

SP - 803

EP - 811

ER -