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 degrees 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.
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D016264:Dextran Sulfate; D003911:Dextrans / Q000494:pharmacology*; D007728:Kupffer Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D012157:Mononuclear Phagocyte System / Q000187:drug effects*
D003911:Dextrans; D003577:Cytochrome P-450 Enzyme System; D016264:Dextran Sulfate; D001189:Aryl Hydrocarbon Hydroxylases