Comparison of the hepatotoxicity of coumarin in the rat, mouse, and Syrian hamster: a dose and time response study.
The effects of coumarin treatment have been compared in male Sprague-Dawley CD rats, male CD-1 mice, and male Syrian hamsters. Rats were fed 0-0.75% coumarin for 1 and 4 weeks and 0-0.5% coumarin for 13 weeks, whereas mice and Syrian hamsters were fed 0-0.5 and 0-1.0% coumarin, respectively, for periods of 1, 4, and 13 weeks. In the rat, coumarin produced dose-related hepatotoxic effects which included vacuolar degeneration, apoptosis, and bile duct proliferation. These effects were particularly marked at dose levels of 0.3 and 0.5%, where liver tumors have been observed in a chronic study. Coumarin administration to rats also increased serum bilirubin content and both serum and hepatic gamma-glutamyltransferase activity. While levels of hepatic total glutathione were increased by coumarin administration, microsomal cytochrome P450 content and ethylmorphine N-demethylase activity were reduced. Such effects were either less marked or absent in the mouse and Syrian hamster. Replicative DNA synthesis was studied by implanting osmotic pumps containing 5-bromo-2'-deoxyuridine during Study Weeks 0-1, 3-4, and 12-13. In the rat, coumarin administration for 4 and 13 weeks at dose levels of 0.3 and 0.5% produced a sustained stimulation of hepatocyte replicative DNA synthesis. No such effects were observed in the mouse and Syrian hamster. These results demonstrate marked species differences in coumarin-induced hepatotoxicity. While tumor formation in the rat appears due to chronic hepatotoxicity associated with a sustained regenerative hyperplasia, such effects were not observed in the CD-1 mouse and Syrian hamster. In assessing the hazard of coumarin to humans, account needs to be taken of both levels of exposure and species differences in response.
Lake
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BIBRA International, Surrey, England.
Grasso
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D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001663:Bilirubin / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D003374:Coumarins / Q000008:administration & dosage / Q000633:toxicity*; D006224:Cricetinae; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005247:Feeding Behavior / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013997:Time Factors; D005723:gamma-Glutamyltransferase / Q000097:blood
D003374:Coumarins; C030123:coumarin; D005723:gamma-Glutamyltransferase; D000410:Alanine Transaminase; D001663:Bilirubin