Gene expression profiling of methapyrilene-induced hepatotoxicity in rat.
The present study was conducted as a model case of the toxicogenomics approach for analyzing toxicological mechanisms and toxicity assessments in the early stage of drug development by comparing with classical toxicology data. Methapyrilene (MP) 100 mg/kg produced obvious histopathological changes in liver of rats by single or repeated dose up to 28 days with significant elevation of ALT and AST. In the middle dose groups (30 mg/kg MP), no apparent changes were noted in blood biochemical data by single dosing or repeated dosing up to one week, and no obvious histopathological changes were observed except a slight hypertrophy in the hepatocytes. Comprehensive gene expression changes were analyzed using Affymetrix GeneChip and differentially expressed probe sets were statistically extracted. These contained many genes related to "glutathione metabolism", "apoptosis", "MAPK signaling pathway" and "regulation of cell cycle", which were all thought to be involved in the development of presently observed phenotypes. In the high dose groups, TGP1 scores (developed in our system in order to overview the responsiveness of drugs to multiple marker gene lists) for these categories were markedly increased from the early time point after single dose and kept their high expression throughout the repeated dose period. In the middle dose groups, the increment of the scores were noted not only at the time points when apparent pathological changes emerged, but also at the earlier stage of repeated dosing and even after single dosing. We conclude that toxicogenomics would enable a more sensitive assessment at the earlier time point than classical toxicology evaluation.
Uehara
Takeki
T
Toxicogenomics Project, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan.
Kiyosawa
Naoki
N
Hirode
Mitsuhiro
M
Omura
Ko
K
Shimizu
Toshinobu
T
Ono
Atsushi
A
Mizukawa
Yumiko
Y
Miyagishima
Toshikazu
T
Nagao
Taku
T
Urushidani
Tetsuro
T
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D002453:Cell Cycle / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D008107:Liver Diseases / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008297:Male; D008701:Methapyrilene / Q000633:toxicity*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D043922:Toxicogenetics
D008701:Methapyrilene; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione