Gene expression profiling of methapyrilene-induced hepatotoxicity in rat

Abstract

-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.

Identification of classifier genes for hepatotoxicity prediction in non steroidal anti inflammatory drugs

“…The ultimate purpose of toxicogenomics is developing a toxicity prediction system using suitable classifier probes through microarray techniques as a replacement of traditional toxicity tests 2,10, [16][17][18][21][22][23][24][25][26][27] . Also, it is important to accumulate data on classifier probes of sufficient numbers of drugs in order to predict, but there are studies using only a few drugs 8,28,29 .…”

Evaluation of DNA microarray results in the Toxicogenomics Project (TGP) consortium in Japan

“…The purpose of TGP2 was to identify biomarkers for diagnosing and/or predicting compound toxicity based upon the gene expression data accumulated in TGP1. A number of biomarkers and gene expression profiles indicative of exposure to particular toxic compounds were reported following the TGP1 and TGP2 studies (Kiyosawa et al, 2006;Morishita et al, 2006;Tamura et al, 2006aTamura et al, , 2006bKiyosawa et al, 2007;Omura et al, 2007;Hirode et al, 2008Hirode et al, , 2009aHirode et al, and 2009bUehara et al, 2008aUehara et al, , 2008bUehara et al, and 2008cKondo et al, 2009;Minowa et al, 2012). Prior to use of the gene expression data accumulated during TGP1 in future drug discovery studies, the procedures used to analyze gene expression must be validated and the degree of inter-laboratory variation must be assessed.…”

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

“…With the advent of microarray expression profiling techniques, several attempts have been made to address induction of liver toxicity in short-term rodent experiments during the preclinical phase of drug development [7][8][9][10]. These studies have shown that hepatotoxicants induce a distinct pattern of deregulated genes at an early stage that may allow detection of arising hepatic toxicity.…”