Toxicity of the antitumoral drug datelliptium in hepatic cells: Use of models in vitro for the prediction of toxicity in vivo.
Datelliptium is a DNA-intercalating agent derived from ellipticine. The drug has potent antitumoral activity in vitro and in vivo. The first clinical use of the drug revealed unexpected hepatotoxic effects in humans that had not been observed in animals. Using different hepatic models in vitro (rat hepatocytes in suspension and in culture, cultured human hepatocytes and rat and human hepatoma cell lines), the possibility of prediction in vitro of the hepatic toxicity of a drug has been investigated. Cytotoxic effects were evaluated by measuring the leakage of intracellular lactate dehydrogenase and the ability of cells to reduce MTT after exposure to concentrations of datelliptium ranging from 0.1 to 1000 mum. According to these endpoint parameters, the concentrations of the drug that produced 50% of maximal inhibitory effect (IC(50)) were in the range 100 to 195 mum in rat hepatocyte suspension and hepatocyte cultures after 2 hr of treatment, 7-9 mum in cultured rat and human hepatocytes after 23 hr of treatment, and about 200-320 mum in HepG2 and FaO cells after 23 hr of treatment. Metabolic parameters were generally more sensitive than cytotoxic endpoints for detecting toxic effects of datelliptium on hepatocytes in the two experimental models used. Metabolic effects on rat hepatocyte suspension and culture were evaluated respectively after 2 and 23 hr of exposure to the drug. Triglyceride secretion was the most sensitive parameter and the IC(10) values (concentration causing 10% of maximal inhibitory effect) were 0.03 and 0.9 mum in hepatocyte suspension and culture, respectively. Glycogen, albumin and cellular protein synthesis were similarly altered in both cellular systems and the IC(10) values were in the range 0.5-3.5 mum. Ureogenesis and gluconeogenesis were relatively insensitive parameters in cell suspensions (IC(10) values 16.4 and 10.3 mum, respectively) compared with those in hepatocyte culture (IC(10) values 3.6 and 3.1 mum, respectively). The concentrations of datelliptium reported in blood, and particularly in liver, are higher than the concentrations that produce impairment of cell metabolism in vitro. This may be an indicator of the toxicological risk of datelliptium and anticipates the hepatotoxicity observed in vivo.
Donato
M T
MT
Unidad de Hepatologia Experimental, Centro de Investigación, Hospital Universitario "La Fe", SVS Avda Campanar 21, E-46009 Valencia, Spain.
Goethals
F
F
Gómez-Lechón
M J
MJ
Deboyser
D
D
De Coster
I
I
Roberfroid
M
M
Castell
J V
JV