Relationship between hepatic gene expression profiles and hepatotoxicity in five typical hepatotoxicant-administered rats.
In the field of gene expression analysis, DNA microarray technology has a major impact on many different areas including toxicogenomics, such as in predicting the adverse effects of new drug candidates and improving the process of risk assessment and safety evaluation. In this study, we investigated whether there is relationship between the hepatotoxic phenotypes and gene expression profiles of hepatotoxic chemicals measured by DNA microarray analyses. Sprague-Dawley rats (6 weeks old) were administered five hepatotoxicants: acetaminophen (APAP), bromobenzene, carbon tetrachloride, dimethylnitrosamine, and thioacetamide. Serum biochemical markers for liver toxicity were measured to estimate the maximal toxic time of each chemical. Hepatic mRNA was isolated, and the gene expression profiles were analyzed by DNA microarray containing 1,097 drug response genes, such as cytochrome P450s, other phase I and phase II enzymes, nuclear receptors, signal transducers, and transporters. All the chemicals tested generated specific gene expression patterns. APAP was sorted to a different cluster from the other four chemicals. From the gene expression profiles and maximal toxic time estimated by serum biochemical markers, we identified 10 up-regulated genes and 10 down-regulated genes as potential markers of hepatotoxicity. By Quality-Threshold (QT) clustering analysis, we identified major up- and down-regulated expression patterns in each group. Interestingly, the average gene expression patterns from the QT clustering were correlated with the mean value profiles from the biochemical markers. Furthermore, this correlation was observed at any extent of hepatotoxicity. In this study, we identified 17 potential toxicity markers, and those expression profiles could estimate the maximal toxic time independently of the hepatotoxicity levels. This expression profile analysis could be one of the useful tools for evaluating a potential hepatotoxicant in the drug development process.
Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan.
Keiichi
K
Minami
Toshiro
T
Saito
Masatoshi
M
Narahara
Hiroyuki
H
Tomita
Hirokazu
H
Kato
Hisashi
H
Sugiyama
Miki
M
Katoh
Miki
M
Nakajima
Tsuyoshi
T
Yokoi
D000082:Acetaminophen / Q000633:toxicity; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001969:Bromobenzenes / Q000633:toxicity; D002251:Carbon Tetrachloride / Q000633:toxicity; D004128:Dimethylnitrosamine / Q000633:toxicity; D020869:Gene Expression Profiling; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013853:Thioacetamide / Q000633:toxicity
D001969:Bromobenzenes; D013853:Thioacetamide; D000082:Acetaminophen; D002251:Carbon Tetrachloride; C032036:bromobenzene; D007770:L-Lactate Dehydrogenase; D000469:Alkaline Phosphatase; D004128:Dimethylnitrosamine