Studies on the disposition, metabolism and hepatotoxicity of coumarin in the rat and Syrian hamster.
The hepatotoxicity, metabolism and disposition of coumarin has been compared in male Sprague-Dawley rats and Syrian hamsters. The treatment of rats for 12, 24 and 42 weeks with diets containing 0.2 and 0.5% coumarin resulted in hepatotoxicity and increased relative liver weights. While levels of cytochrome P450 (CYP) and CYP-dependent enzymes were decreased, levels of reduced glutathione (GSH) and activities of UDP glucuronosyltransferase, gamma-glutamyltransferase and GSH S-transferase were increased. In contrast, coumarin produced few hepatic changes in the Syrian hamster. Following a single oral dose of 25 mg/kg [3-14C]coumarin, radioactivity was rapidly excreted by the rat and Syrian hamster with the urine containing 63.5 and 89.9%, respectively, and the faeces 38.0 and 12.4%, respectively, of the administered dose after 96 h. The biliary excretion of radioactivity was greater in the rat than in the Syrian hamster. Analysis of 0-24-h urine samples revealed that both species were poor 7-hydroxylators of coumarin. In the rat, treatment with 0.5% coumarin in the diet for 24 weeks was found to increase the urinary excretion of single oral gavage doses of 25 and 300 mg/kg [3-14C]coumarin. The marked species difference in hepatotoxicity between the rat and Syrian hamster observed in this study may be at least partially attributable to differences in coumarin disposition. However, additional studies are required to elucidate the metabolic pathways of coumarin in both species.
Lake
B G
BG
TNO BIBRA International Ltd, Woodmansterne Road, Carshalton, Surrey SM5 4DS, UK. blake@tnobibra.co.uk
Evans
J G
JG
Chapuis
F
F
Walters
D G
DG
Price
R J
RJ
D000818:Animals; D000925:Anticoagulants / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology*; D003374:Coumarins / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D006224:Cricetinae; D003600:Cytosol / Q000201:enzymology; D004032:Diet; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D008647:Mesocricetus; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014018:Tissue Distribution
D000925:Anticoagulants; D003374:Coumarins; D005978:Glutathione