COMPARISON OF IN-VIVO AND IN-VITRO RAT HEPATIC TOXICITY OF COUMARIN AND METHYL ANALOGS, AND APPLICATION OF QUANTITATIVE MORPHOMETRY TO TOXICITY IN-VIVO

The rat hepatic toxicity of coumarin and methyl analogues (3-, 4-methyl coumarin and 3,4-dimethylcoumarin) has been determined in vivo and in vitro (freshly-isolated cells). Coumarin at a dose of similar to 1 mmol/kg produced clear histological evidence of centrilobular necrosis, while the methyl analogues at an equivalent dose were much less toxic. By use of a systematic random sampling protocol and quantitative morphometry it was determined that there was a lobar variation in the extent of hepatic damage but that this exhibited random inter-animal variation. The order of cytotoxicity in vitro was identical to that observed in vivo. In hepatocytes depleted of glutathione the toxicity of all four compounds was increased. This was particularly marked for the 3-methyl analogues, such that the order of toxicity was different to that observed in vivo and in hepatocytes not depleted of glutathione.