title: A toxicogenomics-based parallelogram approach to evaluate the relevance of coumarin-induced responses in primary human hepatocytes in vitro for humans in vivo.
abstract: A compound for which marked species differences have been reported in laboratory animals and humans is coumarin. In rats, metabolites of coumarin are highly toxic, whereas in humans, the compound is mainly metabolized to non-toxic metabolites. In the present study, a toxicogenomics-based parallelogram approach was used to compare effects of coumarin on gene expression in human hepatocytes relevant for the situation in vivo. To this purpose, gene expression profiling was performed on human hepatocytes treated with coumarin in a pharmacological relevant and proposed toxic concentration and results were compared to a previously performed coumarin in vivo and in vitro rat toxicogenomics study. No cytotoxicity was observed in human hepatocytes at both concentrations, whereas rats showed clear toxic effects in vitro as well as in vivo. In all three systems, coumarin affected genes involved in the blood coagulation pathway; this indicates relevant responses in cases of human exposure. However, no pathways and processes related to hepatotoxicity in rats were observed in human hepatocytes. Still, repression of energy-consuming biochemical pathways and impairment of mitochondrial function were observed in human hepatocytes treated with the highest concentration of coumarin, possibly indicating toxicity. In conclusion, although species differences in response to coumarin are evident in the present results, the toxicogenomics-based parallelogram approach enables clear discrimination between pharmacological responses at pharmacological doses and proposed toxic responses at high (toxic) doses relevant for humans in vivo.
authors.affiliation: Department of Health Risk Analysis and Toxicology, Maastricht University, Maastricht, The Netherlands. anne.kienhuis@rivm.nl
authors.forename: Anne S
authors.initials: AS
authors.lastname: Kienhuis
authors.forename: Marcel C G
authors.initials: MC
authors.lastname: van de Poll
authors.forename: Cornelis H C
authors.initials: CH
authors.lastname: Dejong
authors.forename: Ralph
authors.initials: R
authors.lastname: Gottschalk
authors.forename: Marcel
authors.initials: M
authors.lastname: van Herwijnen
authors.forename: André
authors.initials: A
authors.lastname: Boorsma
authors.forename: Jos C S
authors.initials: JC
authors.lastname: Kleinjans
authors.forename: Rob H
authors.initials: RH
authors.lastname: Stierum
authors.forename: Joost H M
authors.initials: JH
authors.lastname: van Delft
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000633:toxicity; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D003374:Coumarins / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013045:Species Specificity; D043922:Toxicogenetics / Q000379:methods*
chemical_list: D000925:Anticoagulants; D003374:Coumarins; C030123:coumarin