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Effect of two 5-HT6 receptor antagonists on the rat liver: a molecular approach

The Pharmacogenomics Journal volume 3, pages 320–334 (2003)Cite this article

ABSTRACT

Serotonin is involved in disorders of the central nervous system; thus, specific 5-HT6 receptor antagonists have therapeutic potential. Nevertheless, preclinical tests showed that Ro 65-7199 caused hepatic steatosis. Here, we investigated the hepatic effects of Ro 65-7199 and Ro 66-0074 using toxicogenomics. The profiles obtained after exposure of rats to both compounds clearly show that two pharmacologically closely related compounds with different toxicological profiles can be distinguished based on gene expression profiles. Moreover, side effects can be detected earlier with toxicogenomics than with conventional end points. A possible link between the sterol metabolic pathway, the induction of CYP2B, and the hepatic fat accumulation was also established. Summarizing, gene expression profiles allow both compounds to be distinguished according to their toxicity and provide mechanistic insights. The results clearly show the power of toxicogenomics as a tool for obtaining characteristic fingerprints at early time-points and for generating mechanistic hypotheses.

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Abbreviations

ALT:

alanine aminotransferase

AST:

aspartate aminotransferase

γ-GT:

γ-glutathione transferase

5-HT:

serotonin

LDH:

lactate dehydrogenase

5-ND:

5′-nucleotidase

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Acknowledgements

We would like to thank Ms Simona Romer for her excellent technical assistance. Special thanks go to Dr Rodolfo Gasser, Prof. Ulrich Certa, and Dr Franziska Boess for the many fruitful scientific discussions and their constant support, as well as for their critical reading of the manuscript. We are also deeply indebted to Dr Martin Neeb, Detlef Wolf, Clemens Broger, and the Bioinformatics group at F Hoffmann-La Roche AG for providing the tools and the assistance that made possible the data analysis.

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  1. F Hoffmann-La Roche Ltd, Toxicology, Grenzacherstrasse, Basle, Switzerland

    L Suter, M Haiker, M C de Vera & S Albertini

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  1. L Suter
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  2. M Haiker
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  3. M C de Vera
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  4. S Albertini
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Correspondence to L Suter.

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Suter, L., Haiker, M., de Vera, M. et al. Effect of two 5-HT6 receptor antagonists on the rat liver: a molecular approach. Pharmacogenomics J 3, 320–334 (2003). https://doi.org/10.1038/sj.tpj.6500207

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