Toxicity of heparin in isolated rat hepatocytes

The effect of heparin on isolated rat hepatocytes in monolayer culture was assessed to investigate the observed increase in serum aminotransferase activity in patients treated with heparin for thromboembolic disorders. Cells were treated with porcine intestinal mucosal heparin or beef lung heparin in concentrations ranging from 0.01 to 100 units/ml. Toxicity was evaluated based on cell damage or death measured by LDH release into the culture media as a fraction of total system LDH (LDH index). Toxicity appeared at concentrations between 1 and 10 units/ml (P less than 0.05). The uptake and binding of heparin by the hepatocyte were evaluated by addition of tritium-labeled heparin to the cultures. Sucrose gradient centrifugation with isolation of the liver plasma membranes (LPM) showed little membrane binding of heparin. The majority of intracellular heparin was located in the cytosol fraction. Heparin gains access to hepatocytes and causes a dose-related toxic effect resulting in cell damage and death. This investigation indicates that the increased serum aminotransferase concentrations seen with heparin treatment may be due to a direct hepatotoxic effect of heparin.