Assessment of hepatotoxic liabilities by transcript profiling.
Male Wistar rats were treated with various model compounds or the appropriate vehicle controls in order to create a reference database for toxicogenomics assessment of novel compounds. Hepatotoxic compounds in the database were either known hepatotoxicants or showed hepatotoxicity during preclinical testing. Histopathology and clinical chemistry data were used to anchor the transcript profiles to an established endpoint (steatosis, cholestasis, direct acting, peroxisomal proliferation or nontoxic/control). These reference data were analyzed using a supervised learning method (support vector machines, SVM) to generate classification rules. This predictive model was subsequently used to assess compounds with regard to a potential hepatotoxic liability. A steatotic and a non-hepatotoxic 5HT(6) receptor antagonist compound from the same series were successfully discriminated by this toxicogenomics model. Additionally, an example is shown where a hepatotoxic liability was correctly recognized in the absence of pathological findings. In vitro experiments and a dog study confirmed the correctness of the toxicogenomics alert. Another interesting observation was that transcript profiles indicate toxicologically relevant changes at an earlier timepoint than routinely used methods. Together, these results support the useful application of toxicogenomics in raising alerts for adverse effects and generating mechanistic hypotheses that can be followed up by confirmatory experiments.
F. Hoffmann-La Roche Ltd., PRBN-S (90/5.18), CH-4070 Basel, Switzerland. stefan.ruepp@roche.com
Stefan
S
Ruepp
Franziska
F
Boess
Laura
L
Suter
Maria Cristina
MC
de Vera
Guido
G
Steiner
Thomas
T
Steele
Thomas
T
Weiser
Silvio
S
Albertini
D000818:Animals; D004285:Dogs; D020869:Gene Expression Profiling; D008099:Liver / Q000187:drug effects*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects; D018675:Toxicity Tests
D012333:RNA, Messenger; D011985:Receptors, Serotonin; C097216:serotonin 6 receptor