Species-specific differences in coumarin-induced hepatotoxicity as an example toxicogenomics-based approach to assessing risk of toxicity to humans

T. Uehara, N. Kiyosawa, T. Shimizu, K. Omura, M. Hirode, T. Imazawa, Y. Mizukawa, Atsushi Ono, T. Miyagishima, T. Nagao, Tetsuro Urushidani

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

One expected result from toxicogenomics technology is to overcome the barrier because of species-specific differences in prediction of clinical toxicity using animals. The present study serves as a model case to test if the well-known species-specific difference in the toxicity of coumarin could be elucidated using comprehensive gene expression data from rat in-vivo, rat in-vitro, and human in-vitro systems. Coumarin 150 mg/kg produced obvious pathological changes in the liver of rats after repeated administration for 7 days or more. Moreover, 24 h after a single dose, we observed minor and transient morphological changes, suggesting that some early events leading to hepatic injury occur soon after coumarin is administered to rats. Comprehensive gene expression changes were analyzed using an Affymetrix GeneChip® approach, and differentially expressed probe sets were statistically extracted. The changes in expression of the selected probe sets were further examined in primary cultured rat hepatocytes exposed to coumarin, and differentially expressed probe sets common to the in-vivo and in-vitro datasets were selected for further study. These contained many genes related to glutathione metabolism and the oxidative stress response. To incorporate human data, human hepatocyte cultured cells were exposed to coumarin and changes in expression of the bridging gene set were examined. In total, we identified 14 up-regulated and 11 down-regulated probe sets representing rat-human bridging genes. The overall responsiveness of these genes to coumarin was much higher in rats than humans, consistent with the reported species difference in coumarin toxicity. Next, we examined changes in expression of the rat-human bridging genes in cultured rat and human hepatocytes treated with another hepatotoxicant, diclofenac sodium, for which hepatotoxicity does not differ between the species. Both rat and human hepatocytes responded to the marker genes to the same extent when the same concentrations of diclofenac sodium were exposed. We conclude that toxicogenomics-based approaches show promise for overcoming species-specific differences that create a bottleneck in analysis of the toxicity of potential therapeutic treatments.

Original languageEnglish
Pages (from-to)23-35
Number of pages13
JournalHuman and Experimental Toxicology
Volume27
Issue number1
DOIs
Publication statusPublished - Jan 2008
Externally publishedYes

Fingerprint

Toxicogenetics
Toxicity
Rats
Genes
Hepatocytes
Diclofenac
Gene Expression
Gene expression
coumarin
Oxidative stress
Liver
Metabolism
Glutathione
Cultured Cells
Animals
Oxidative Stress
Cells

Keywords

  • Coumarin
  • Hepatocyte
  • Hepatotoxicity
  • Human
  • Liver
  • Rat
  • Toxicogenomics

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Species-specific differences in coumarin-induced hepatotoxicity as an example toxicogenomics-based approach to assessing risk of toxicity to humans. / Uehara, T.; Kiyosawa, N.; Shimizu, T.; Omura, K.; Hirode, M.; Imazawa, T.; Mizukawa, Y.; Ono, Atsushi; Miyagishima, T.; Nagao, T.; Urushidani, Tetsuro.

In: Human and Experimental Toxicology, Vol. 27, No. 1, 01.2008, p. 23-35.

Research output: Contribution to journalArticle

Uehara, T, Kiyosawa, N, Shimizu, T, Omura, K, Hirode, M, Imazawa, T, Mizukawa, Y, Ono, A, Miyagishima, T, Nagao, T & Urushidani, T 2008, 'Species-specific differences in coumarin-induced hepatotoxicity as an example toxicogenomics-based approach to assessing risk of toxicity to humans', Human and Experimental Toxicology, vol. 27, no. 1, pp. 23-35. https://doi.org/10.1177/0960327107087910
Uehara, T. ; Kiyosawa, N. ; Shimizu, T. ; Omura, K. ; Hirode, M. ; Imazawa, T. ; Mizukawa, Y. ; Ono, Atsushi ; Miyagishima, T. ; Nagao, T. ; Urushidani, Tetsuro. / Species-specific differences in coumarin-induced hepatotoxicity as an example toxicogenomics-based approach to assessing risk of toxicity to humans. In: Human and Experimental Toxicology. 2008 ; Vol. 27, No. 1. pp. 23-35.
@article{238a1055e60f4eebb5223d62e80b063e,
title = "Species-specific differences in coumarin-induced hepatotoxicity as an example toxicogenomics-based approach to assessing risk of toxicity to humans",
abstract = "One expected result from toxicogenomics technology is to overcome the barrier because of species-specific differences in prediction of clinical toxicity using animals. The present study serves as a model case to test if the well-known species-specific difference in the toxicity of coumarin could be elucidated using comprehensive gene expression data from rat in-vivo, rat in-vitro, and human in-vitro systems. Coumarin 150 mg/kg produced obvious pathological changes in the liver of rats after repeated administration for 7 days or more. Moreover, 24 h after a single dose, we observed minor and transient morphological changes, suggesting that some early events leading to hepatic injury occur soon after coumarin is administered to rats. Comprehensive gene expression changes were analyzed using an Affymetrix GeneChip{\circledR} approach, and differentially expressed probe sets were statistically extracted. The changes in expression of the selected probe sets were further examined in primary cultured rat hepatocytes exposed to coumarin, and differentially expressed probe sets common to the in-vivo and in-vitro datasets were selected for further study. These contained many genes related to glutathione metabolism and the oxidative stress response. To incorporate human data, human hepatocyte cultured cells were exposed to coumarin and changes in expression of the bridging gene set were examined. In total, we identified 14 up-regulated and 11 down-regulated probe sets representing rat-human bridging genes. The overall responsiveness of these genes to coumarin was much higher in rats than humans, consistent with the reported species difference in coumarin toxicity. Next, we examined changes in expression of the rat-human bridging genes in cultured rat and human hepatocytes treated with another hepatotoxicant, diclofenac sodium, for which hepatotoxicity does not differ between the species. Both rat and human hepatocytes responded to the marker genes to the same extent when the same concentrations of diclofenac sodium were exposed. We conclude that toxicogenomics-based approaches show promise for overcoming species-specific differences that create a bottleneck in analysis of the toxicity of potential therapeutic treatments.",
keywords = "Coumarin, Hepatocyte, Hepatotoxicity, Human, Liver, Rat, Toxicogenomics",
author = "T. Uehara and N. Kiyosawa and T. Shimizu and K. Omura and M. Hirode and T. Imazawa and Y. Mizukawa and Atsushi Ono and T. Miyagishima and T. Nagao and Tetsuro Urushidani",
year = "2008",
month = "1",
doi = "10.1177/0960327107087910",
language = "English",
volume = "27",
pages = "23--35",
journal = "Human and Experimental Toxicology",
issn = "0960-3271",
publisher = "SAGE Publications Inc.",
number = "1",

}

TY - JOUR

T1 - Species-specific differences in coumarin-induced hepatotoxicity as an example toxicogenomics-based approach to assessing risk of toxicity to humans

AU - Uehara, T.

AU - Kiyosawa, N.

AU - Shimizu, T.

AU - Omura, K.

AU - Hirode, M.

AU - Imazawa, T.

AU - Mizukawa, Y.

AU - Ono, Atsushi

AU - Miyagishima, T.

AU - Nagao, T.

AU - Urushidani, Tetsuro

PY - 2008/1

Y1 - 2008/1

N2 - One expected result from toxicogenomics technology is to overcome the barrier because of species-specific differences in prediction of clinical toxicity using animals. The present study serves as a model case to test if the well-known species-specific difference in the toxicity of coumarin could be elucidated using comprehensive gene expression data from rat in-vivo, rat in-vitro, and human in-vitro systems. Coumarin 150 mg/kg produced obvious pathological changes in the liver of rats after repeated administration for 7 days or more. Moreover, 24 h after a single dose, we observed minor and transient morphological changes, suggesting that some early events leading to hepatic injury occur soon after coumarin is administered to rats. Comprehensive gene expression changes were analyzed using an Affymetrix GeneChip® approach, and differentially expressed probe sets were statistically extracted. The changes in expression of the selected probe sets were further examined in primary cultured rat hepatocytes exposed to coumarin, and differentially expressed probe sets common to the in-vivo and in-vitro datasets were selected for further study. These contained many genes related to glutathione metabolism and the oxidative stress response. To incorporate human data, human hepatocyte cultured cells were exposed to coumarin and changes in expression of the bridging gene set were examined. In total, we identified 14 up-regulated and 11 down-regulated probe sets representing rat-human bridging genes. The overall responsiveness of these genes to coumarin was much higher in rats than humans, consistent with the reported species difference in coumarin toxicity. Next, we examined changes in expression of the rat-human bridging genes in cultured rat and human hepatocytes treated with another hepatotoxicant, diclofenac sodium, for which hepatotoxicity does not differ between the species. Both rat and human hepatocytes responded to the marker genes to the same extent when the same concentrations of diclofenac sodium were exposed. We conclude that toxicogenomics-based approaches show promise for overcoming species-specific differences that create a bottleneck in analysis of the toxicity of potential therapeutic treatments.

AB - One expected result from toxicogenomics technology is to overcome the barrier because of species-specific differences in prediction of clinical toxicity using animals. The present study serves as a model case to test if the well-known species-specific difference in the toxicity of coumarin could be elucidated using comprehensive gene expression data from rat in-vivo, rat in-vitro, and human in-vitro systems. Coumarin 150 mg/kg produced obvious pathological changes in the liver of rats after repeated administration for 7 days or more. Moreover, 24 h after a single dose, we observed minor and transient morphological changes, suggesting that some early events leading to hepatic injury occur soon after coumarin is administered to rats. Comprehensive gene expression changes were analyzed using an Affymetrix GeneChip® approach, and differentially expressed probe sets were statistically extracted. The changes in expression of the selected probe sets were further examined in primary cultured rat hepatocytes exposed to coumarin, and differentially expressed probe sets common to the in-vivo and in-vitro datasets were selected for further study. These contained many genes related to glutathione metabolism and the oxidative stress response. To incorporate human data, human hepatocyte cultured cells were exposed to coumarin and changes in expression of the bridging gene set were examined. In total, we identified 14 up-regulated and 11 down-regulated probe sets representing rat-human bridging genes. The overall responsiveness of these genes to coumarin was much higher in rats than humans, consistent with the reported species difference in coumarin toxicity. Next, we examined changes in expression of the rat-human bridging genes in cultured rat and human hepatocytes treated with another hepatotoxicant, diclofenac sodium, for which hepatotoxicity does not differ between the species. Both rat and human hepatocytes responded to the marker genes to the same extent when the same concentrations of diclofenac sodium were exposed. We conclude that toxicogenomics-based approaches show promise for overcoming species-specific differences that create a bottleneck in analysis of the toxicity of potential therapeutic treatments.

KW - Coumarin

KW - Hepatocyte

KW - Hepatotoxicity

KW - Human

KW - Liver

KW - Rat

KW - Toxicogenomics

UR - http://www.scopus.com/inward/record.url?scp=44849119956&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=44849119956&partnerID=8YFLogxK

U2 - 10.1177/0960327107087910

DO - 10.1177/0960327107087910

M3 - Article

VL - 27

SP - 23

EP - 35

JO - Human and Experimental Toxicology

JF - Human and Experimental Toxicology

SN - 0960-3271

IS - 1

ER -