title: An in vitro study on 5-HT6 receptor antagonist induced hepatotoxicity based on biochemical assays and toxicogenomics.
abstract: We investigated the effects of two 5-HT(6) receptor antagonists on rat primary hepatocytes using a combined biochemical and toxicogenomics approach. Both compounds share the same pharmacological target, but displayed strikingly different toxicity profiles in pre-clinical animal studies: While R7199 caused hepatic steatosis in rats, no hepatotoxicity was observed with R0074. Here, we partially reproduced the steatosis findings seen in vivo using primary rat hepatocytes. Biochemical analyses and gene expression results generally supported the findings observed in the animal model and also allowed the differentiation of both compounds with regards to hepatotoxic potential. In particular, the induction of Cyp 2B and Cyp 3A1 directly correlates to the findings in the livers of treated animals. The effects on genes of the steroideogenic pathway relate to the deregulation of cholesterol homeostasis. We also observed the inhibition of beta-oxidation, indicating impaired lipid metabolism. Hence, gene expression analysis in combination with biochemical parameters can provide additional insight into the possible mechanisms underlying adverse events.
authors.affiliation: F. Hoffmann-La Roche AG, Toxicology Department, 4070 Basel, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Boess
authors.forename: E
authors.initials: E
authors.lastname: Durr
authors.forename: N
authors.initials: N
authors.lastname: Schaub
authors.forename: M
authors.initials: M
authors.lastname: Haiker
authors.forename: S
authors.initials: S
authors.lastname: Albertini
authors.forename: L
authors.initials: L
authors.lastname: Suter
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000187:drug effects / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D004790:Enzyme Induction / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000473:pathology; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000633:toxicity*; D043922:Toxicogenetics / Q000379:methods*
chemical_list: D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor; D002784:Cholesterol; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A