In vitro gene expression analysis of hepatotoxic drugs in rat primary hepatocytes.
The study examined the feasibility of screening for hepatotoxicity by an in vitro gene expression analysis using rat primary hepatocytes and Affymetrix Rat Toxicology U34 arrays. Hepatocytes were exposed for 6 or 24 h to eight drugs, with different mechanisms of hepatotoxicity, at one third of the cytotoxic concentration TC50, i.e. acetaminophen, cyclophosphamide, clofibrate, chlorpromazine, lithocholic acid, cisplatin, diclofenac and disulfiram. The types of transcriptional changes observed in this study were generally consistent with previously reported in vivo data, although there were some differences. In hierarchical cluster analysis, drugs formed clusters depending on their mode of toxicity against cells. The number of transcripts affected by the cholestatic hepatotoxicants (lithocholic acid and chlorpromazine) or the drugs that rarely cause of hepatotoxicity (cisplatin, diclofenac and disulfiram) were limited compared with the other drugs (acetaminophen, clobifibrate and cyclophosphamide), where they did not induce transcriptional changes apparently related to toxicity. It is concluded that in vitro gene expression analysis of hepatocytes using microarray is a useful tool for evaluating the toxicological profile of drugs and in screening for the direct toxicity of drugs against hepatocytes.
Suzuki
Hiromi
H
Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. suzukihrm@chugai-pharm.co.jp
Inoue
Tomoaki
T
Matsushita
Tomochika
T
Kobayashi
Kazuko
K
Horii
Ikuo
I
Hirabayashi
Yoko
Y
Inoue
Tohru
T
D000082:Acetaminophen / Q000633:toxicity; D000818:Animals; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002994:Clofibrate / Q000633:toxicity; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D020869:Gene Expression Profiling / Q000379:methods*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods*; D014158:Transcription, Genetic / Q000187:drug effects*
D012333:RNA, Messenger; D000082:Acetaminophen; D002994:Clofibrate