METABOLISM AND TOXICITY OF COUMARIN ON CULTURED HUMAN, RAT, MOUSE ANDRABBIT HEPATOCYTES

We compared the cytotoxic effect of coumarin and its derivatives, 7-hy droxycoumarin (7-OHC), 4-hydroxycoumarin (4-OHC), o-hydroxyphenyl acet ic 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, couma rin 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 n ot its derivatives, induced release of lactate dehydrogenase (LDH) int o the medium, especially in rat hepatocyte cultures. Intracellular LDH activities were correspondingly reduced. The cytotoxic effect of coum arin in cultured rat hepatocytes was evidenced on morphological examin ation and from the results of the (4,5-dimethylthiazol-2-yl)-2,5-diphe nyltetrazolium (MTT) reduction test. At higher concentrations (5 x 10( -4) M), 7-OHC and CA were also found to be cytotoxic in cultured rat h epatocytes. The cytotoxic effect of coumarin (5 x 10(-4) M) was decrea sed in the presence of SKF 525-A, a cytochrome P450 inhibitor. Intersp ecies comparisons showed that rat hepatocytes were the most sensitive to the toxicity of coumarin and its derivatives, whereas human hepatoc ytes were the most resistant. Our results suggest that the cytotoxicit y of coumarin is metabolism and species-dependent. Thus, the rat may n ot be a suitable model for evaluating the pharmacological hazards of c oumarin in humans.