Molecular profiling of hepatotoxicity induced by a aminoguanidine carboxylate in the rat: gene expression profiling.
The hepatotoxicity of the aminoguanidine carboxylate 2-[1-[hydrazino(imino)methyl]hydrazino]acetic acid was characterized using oligonucleotide micro arrays, with the goal to select compounds from the same class with lower toxicity potential. The approach included a 14-day repeated- and a single-dose study in the rat as well as in vitro studies. Common gene expression changes could be followed from in vivo to in vitro studies. Anyhow, comparing the in vivo and in vitro response of the compound on gene expression, significant discrepancies were detected. Many of the genes whose mRNA levels were increased/decreased in the livers of the animals treated with toxic doses of the compound, were expressed at higher/lower levels in control hepatocytes than in control liver. The expression of the majority of these genes was not affected by in vitro treatment. These data question the use of gene expression analysis as a marker for drug response in vitro and illustrate the need of a careful characterization of in vitro systems. The results presented show that array-based gene expression analysis can lead to a better understanding of the molecular basis of drug-induced liver injury and, potentially, be used in the selection process for compounds and in the design of safer drugs.
Schuppe-Koistinen
Ina
I
Preclinical Sciences/Molecular Toxicology, Pharmacia Corp., Stockholm, Sweden. ina.schuppe-koistinen@astrazeneca.com
Frisk
Anna-Lena
AL
Janzon
Lars
L
D000085:Acetates / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D001786:Blood Glucose / Q000032:analysis; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D004334:Drug Administration Schedule; D020869:Gene Expression Profiling; D006146:Guanidines / Q000633:toxicity*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D023382:Toxicity Tests, Acute; D014280:Triglycerides / Q000097:blood
C424915:2-(1-(hydrazino(imino)methyl)hydrazino)acetic acid; D000085:Acetates; D001786:Blood Glucose; D006146:Guanidines; D014280:Triglycerides; D002784:Cholesterol; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin