Gene expression profiles in rat liver slices exposed to hepatocarcinogenic enzyme inducers, peroxisome proliferators, and 17alpha-ethinylestradiol.
Transcription profiling is used as an in vivo method for predicting the mode-of-action class of nongenotoxic carcinogens. To set up a reliable in vitro short-term test system DNA microarray technology was combined with rat liver slices. Seven compounds known to act as tumor promoters were selected, which included the enzyme inducers phenobarbital, alpha-hexachlorocyclohexane, and cyproterone acetate; the peroxisome proliferators WY-14,643, dehydroepiandrosterone, and ciprofibrate; and the hormone 17alpha-ethinylestradiol. Rat liver slices were exposed to various concentrations of the compounds for 24 h. Toxicology-focused TOXaminer DNA microarrays containing approximately 1500 genes were used for generating gene expression profiles for each of the test compound. Hierarchical cluster analysis revealed that (i) gene expression profiles generated in rat liver slices in vitro were specific allowing classification of compounds with similar mode of action and (ii) expression profiles of rat liver slices exposed in vitro correlate with those induced after in vivo treatment (reported previously). Enzyme inducers and peroxisome proliferators formed two separate clusters, confirming that they act through different mechanisms. Expression profiles of the hormone 17alpha-ethinylestradiol were not similar to any of the other compounds. In conclusion, gene expression profiles induced by compounds that act via similar mechanisms showed common effects on transcription upon treatment in vivo and in rat liver slices in vitro.
Werle-Schneider
Gisela
G
Division of Toxicology and Cancer Risk Factors, German Cancer Research Center, (DKFZ), Heidelberg, Germany. g.werle@dkfz.de
Wölfelschneider
Andreas
A
von Brevern
Marie Charlotte
MC
Scheel
Julia
J
Storck
Thorsten
T
Müller
Dieter
D
Glöckner
Reinhild
R
Bartsch
Helmut
H
Bartelmann
Matthias
M
D000726:Androgen Antagonists / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002995:Clofibric Acid / Q000031:analogs & derivatives / Q000633:toxicity; D017373:Cyproterone Acetate / Q000633:toxicity; D003687:Dehydroepiandrosterone / Q000633:toxicity; D004790:Enzyme Induction; D004967:Estrogens / Q000633:toxicity; D004997:Ethinyl Estradiol / Q000633:toxicity*; D058607:Fibric Acids; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D001556:Hexachlorocyclohexane / Q000633:toxicity; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008113:Liver Neoplasms; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020025:Peroxisome Proliferators / Q000633:toxicity*; D010634:Phenobarbital / Q000633:toxicity; D011743:Pyrimidines / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar
D000726:Androgen Antagonists; D002273:Carcinogens; D004967:Estrogens; D058607:Fibric Acids; D020025:Peroxisome Proliferators; D011743:Pyrimidines; C040534:alpha-hexachlorocyclohexane; D004997:Ethinyl Estradiol; D003687:Dehydroepiandrosterone; D017373:Cyproterone Acetate; D002995:Clofibric Acid; D001556:Hexachlorocyclohexane; C006253:pirinixic acid; C019304:ciprofibrate; D010634:Phenobarbital