Studies on the disposition, metabolism and hepatotoxicity of coumarin in the rat and Syrian hamster

Comparison of Coumarin-Induced Toxicity between Sandwich-Cultured Primary Rat Hepatocytes and Rats in Vivo: A Toxicogenomics Approach

“…Coumarin, a compound for which toxicity depends on metabolism by the P450 enzyme system, was used as a model compound. Specifically, P450 enzymes of the 1A and 2E subfamilies convert coumarin to the toxic metabolite coumarin 3,4-epoxide (CE) (Born et al, 2002;Lake et al, 2002). CE rearranges spontaneously to the more stable o-hydroxyphenylacetaldehyde (o-HPA).…”

“…Furthermore, upon addition of the inducer mixture, enzyme activities of the 1A subfamily were increased to levels comparable to in vivo (A. S. Kienhuis, H. M. Wortelboer, W. J. Maas, M. van Herwijnen, J. C. S. Kleinjans, J. H. M. Delft, and R. H. Stierum, manuscript submitted for publication). Since coumarin is converted by CYP1A and CYP2E to o-HPA (Born et al, 2002;Lake et al, 2002), this metabolite possibly causes the cytotoxicity in the modified model. It was shown earlier that the compounds in the inducer mixture, PB, DEX, and ␤-NF, increase the formation of o-HPA and other coumarin metabolites, enhancing coumarin toxicity (Peters et al, 1991;Fentem and Fry, 1992).…”

“…In a separate study performed by this laboratory, it was shown that in sandwich-cultured hepatocytes maintained in modified medium, enriched with low concentrations of the known P450 inducers phenobarbital (PB), dexamethasone (DEX), and ␤-naphthoflavone (␤-NF), the metabolic competence, as reflected by retention of P450 enzyme activities and gene expression levels of several phase I and phase II enzymes, was enhanced (A. S. Kienhuis, H. M. Wortelboer, W. J. Maas, M. van Herwijnen, J. C. S. Kleinjans, J. H. M. Delft, and R. H. Stierum, manuscript submitted for publication). In the present study, the effect of coumarin (cis-o-coumaric acid lactone), a compound for which toxicity depends on metabolic activation by the P450 enzyme system (Born et al, 2002;Lake et al, 2002), on toxicity and gene expression profiles was studied in sandwich-cultured hepatocytes maintained in standard medium, the standard model (without inducers), and in sandwich-cultured hepatocytes maintained in modified medium, the modified model (containing enzyme inducers). Coumarin-induced cytotoxicity data and gene expression profiles generated in both in vitro models were compared with toxicity and gene expression profiles in rat liver in the in vivo study in which rats were exposed to coumarin, since in vivo verification of in vitro toxicogenomics data has been proposed to be a necessity to judge the value of the in vitro model for in vivo toxicity prediction (Jaeschke, 2003).…”

Phenprocoumon-induced liver disease ranges from mild acute hepatitis to (sub-) acute liver failure

“…On the other side, a relation to metabolism of the drug and an enhanced susceptibility of the target enzymes, which are inhibited by oral anticoagulants, has been discussed [22]. Coumarin treatment of rats lead to decreased levels of cytochrome P450 (CYP), CYP-dependent enzymes and increased levels of reduced glutathione (GSH) and gamma-glutamyltransferase [49]. However, high-energy-reactions involving cytochrome P-450 enzymes mediating covalent binding of drugs, such as coumarins, to intracellular proteins with consecutive decline of ATP levels, loss of ionic gradients, cell swelling and rupture have been postulated as well [48].…”

The hepatoprotective effect of coumarin and coumarin derivates on carbon tetrachloride-induced hepatic injury by antioxidative activities in rats

“…Coumarin possesses neither a hydroxyl nor a methoxy group. It was indicated that coumarin produced either hepatic necrosis or elevated plasma transaminase activities in rodents [22,23]. However, Marshall [31] and Khan et al [20] showed that coumarin attenuated potassium bromate-and ferric nitrilotriacetate-induced nephrotoxicity by preventing free radical-mediated oxidative stress in rats.…”