Metabolism and toxicity of coumarin on cultured human, rat, mouse and rabbit hepatocytes.
We compared the cytotoxic effect of coumarin and its derivatives, 7-hydroxycoumarin (7-OHC), 4-hydroxycoumarin (4-OHC), o-hydroxyphenyl acetic acid (OHPAA) and o-coumaric acid (CA), on cultured hepatocytes from human, rat, mouse and rabbit liver. At 10(-5) and 5 x 10(-5) M, coumarin and its derivatives did not give rise to any signs of toxicity on cultured hepatocytes of the four species. At 10(-4) M, coumarin, but not its derivatives, induced release of lactate dehydrogenase (LDH) into the medium, especially in rat hepatocyte cultures. Intracellular LDH activities were correspondingly reduced. The cytotoxic effect of coumarin in cultured rat hepatocytes was evidenced on morphological examination and from the results of the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium (MTT) reduction test. At higher concentrations (5 x 10(-4) M), 7-OHC and CA were also found to be cytotoxic in cultured rat hepatocytes. The cytotoxic effect of coumarin (5 x 10(-4) M) was decreased in the presence of SKF 525-A, a cytochrome P450 inhibitor. Interspecies comparisons showed that rat hepatocytes were the most sensitive to the toxicity of coumarin and its derivatives, whereas human hepatocytes were the most resistant. Our results suggest that the cytotoxicity of coumarin is metabolism and species-dependent. Thus, the rat may not be a suitable model for evaluating the pharmacological hazards of coumarin in humans.
Ratanasavanh
D
D
Laboratoire de Pharmacologie, CHU de Brest, France.
Lamiable
D
D
Biour
M
M
Guédès
Y
Y
Gersberg
M
M
Leutenegger
E
E
Riché
C
C
D015110:4-Hydroxycoumarins / Q000378:metabolism / Q000633:toxicity; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D002648:Child; D003373:Coumaric Acids / Q000378:metabolism / Q000633:toxicity; D003374:Coumarins / Q000378:metabolism* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged; D010648:Phenylacetates / Q000378:metabolism / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014468:Umbelliferones / Q000378:metabolism / Q000633:toxicity
D015110:4-Hydroxycoumarins; D003373:Coumaric Acids; D003374:Coumarins; D010648:Phenylacetates; D014468:Umbelliferones; C031477:7-hydroxycoumarin; C030123:coumarin; D007770:L-Lactate Dehydrogenase; C005756:2-hydroxyphenylacetic acid; C068805:4-hydroxycoumarin