Effect of two 5-HT6 receptor antagonists on the rat liver: a molecular approach.
Serotonin is involved in disorders of the central nervous system; thus, specific 5-HT(6) 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.
Suter
L
L
F Hoffmann-La Roche Ltd, Toxicology, Grenzacherstrasse, Basle, Switzerland. laura.suter-dick@roche.com
Haiker
M
M
De Vera
M C
MC
Albertini
S
S
D000818:Animals; D020869:Gene Expression Profiling / Q000379:methods*; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000235:genetics / Q000502:physiology*; D012702:Serotonin Antagonists / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D013450:Sulfones; D000096926:Benzenesulfonamides
D007093:Imidazoles; D007211:Indoles; D011725:Pyridines; D011759:Pyrrolidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013141:Spiro Compounds; D013449:Sulfonamides; D013450:Sulfones; C473484:4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenylamine; C121726:8-acenaphthen-1-yl-1-phenyl-1,3,8-triazaspiro(4.5)decan-4-one; C488333:Ro 65-7199; D000096926:Benzenesulfonamides; C097216:serotonin 6 receptor