In Vitro Model of the Human Liver Parenchyma to Study Hepatotoxic Side Effects of Dy-EOB-DTPA

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Abstract
In vivo studies have shown species-specific toxicity after application of the liver-specific contrast agent Dy-ethoxybenzyl (EOB)-DTPA. To predict species differences in the laboratory, an in vitro model of the liver was used to examine the divergent results. Rat, canine, porcine, and human hepatocytes were isolated and embedded between layers of collagen. During and after 48 hours of incubation with different concentrations of Dy-EOB-DTPA (maximum concentration 50 mmol/L), morphological changes and enzyme leakage were determined. The response to the contrast agent varied for hepatocytes from different species. For canine cells, morphological changes and cell death were evident with as little as 5 mmol/L Dy-EOB-DTPA. Rat hepatocytes tolerated up to 50 mmol/L Dy-EOB-DTPA, and enzyme leakage was transient. Only after incubation with 50 mmol/L Dy-EOB-DTPA was the formation of intracellular vacuoles evident. In contrast, even the highest concentration of Dy-EOB-DTPA did not cause an enzyme leakage of porcine or human hepatocytes, although similar vacuoles were seen. These data demonstrate a species-dependent toxicity for Dy-EOB-DTPA in vitro, with similar responses in porcine and human hepatocytes.