title: Studies on the mechanism of coumarin-induced toxicity in rat hepatocytes.
abstract: Rat hepatocyte suspensions have been used as a model system for some studies on the mechanism of coumarin-induced hepatotoxicity. Hepatocytes were isolated from male Sprague-Dawley rats and subjected to Percoll centrifugation to obtain preparations with >/=92% viability. Coumarin produced time- and concentration-dependent cytotoxic effects in rat hepatocytes as indicated by loss of cell viability and glutathione depletion. [3-(14)C]Coumarin was metabolized by rat hepatocytes to polar metabolites including o-hydroxyphenylacetic acid and to metabolites that became covalently bound to hepatocyte proteins. The addition of 10 mum-ellipticine significantly reduced coumarin cytotoxicity, coumarin metabolism and covalent binding in rat hepatocytes. These results demonstrate that coumarin-induced liver injury in the rat can be modelled in hepatocyte suspensions and that toxicity appears to be due to one or more cytochrome P-450 generated metabolites.
authors.affiliation: Department of Toxicology, Wageningen Agricultural University, 6700 EV Wageningen, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: den Besten
authors.forename: S A
authors.initials: SA
authors.lastname: Körösi
authors.forename: J A
authors.initials: JA
authors.lastname: Beamand
authors.forename: D G
authors.initials: DG
authors.lastname: Walters
authors.forename: B G
authors.initials: BG
authors.lastname: Lake