Depression of Cytochrome P-450-dependent drug biotransformation in hepatocytes after the activation of the reticuloendothelial system by dextran sulfate

Cytochrome P-450 and aryl hydrocarbon hydroxylase were depressed in microsomes prepared from the livers of mice treated with dextran sulfate. Unlike some other immune modulating drugs which decrease cytochrome P-450, dextran sulfate did not induce interferon production in the serum of these animals. Dextran sulfate had no effect on cytochrome P-450 when incubated with isolated hepatocytes alone but with mixtures of hepatocytes and Kupffer cells both cytochrome P-450 and aryl hydrocarbon hydroxylase were significantly depressed. Kupffer cells were then incubated at 37°C for 30 min with dextran sulfate. After centrifugation the resulting cell-free supernatant decreased cytochrome P-450 and aryl hydrocarbon hydroxylase when incubated with hepatocytes. These experiments suggest that dextran sulfate stimulates the release of a factor by Kupffer cells which can decrease cytochrome P-450 in hepatocytes. This was confirmed by incubating cells in a membrane partitioned double-chambered Marbrook vessel to separate cell types and prevent passage of dextran sulfate. When dextran sulfate was added to the chamber containing Kupffer cells a factor was released which crossed a semipermeable membrane and depressed cytochrome P-450 levels in the hepatocytes in the other chamber. It is concluded that dextran sulfate depresses drug biotransformation in the liver via a factor which is released from Kupffer cells.