Fibric acid derivatives: effects on the synthesis of isoprenoid lipids in cultured human lymphocytes.
Fibric acid derivatives have been demonstrated to reduce circulating lipoprotein and triacylglycerol concentrations and to inhibit hydroxymethylglutaryl CoA reductase, a key regulatory enzyme of cholesterol biosynthesis. This study describes the effect of four fibric acid derivatives on the biosynthesis of isoprenoid products from acetate and mevalonate in Molt-4 cells, a human leukemic T-lymphocyte cell line. The isoprenoids analyzed were cholesterol as well as dolichol and ubiquinone, alternative products of the branched isoprenoid biosynthetic pathway. None of the fibric acid derivatives showed significant effects on the synthesis of cholesterol from acetate or mevalonate and there was little change in the flux of these metabolites into either dolichol and ubiquinone compared to cells grown in drug-free medium. Therefore, in contrast to the reported inhibitory effects of fibric acids on hepatic sterol synthesis in rats and humans and on hydroxymethylglutaryl CoA reductase activity in human nonmalignant lymphocytes, our results show that these drugs do not significantly affect any of the post-reductase enzymes in the branched metabolic pathways leading from acetate to dolichol, ubiquinone and cholesterol in short term culturing of human malignant lymphocytes.
Henry
A
A
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville 32610.
Allen
C M
CM
Stacpoole
P W
PW
D000085:Acetates / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis; D002994:Clofibrate / Q000494:pharmacology*; D004286:Dolichols / Q000378:metabolism; D015248:Gemfibrozil / Q000494:pharmacology*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D008798:Mevalonic Acid / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014451:Ubiquinone / Q000096:biosynthesis
D000085:Acetates; D004286:Dolichols; D014451:Ubiquinone; D002784:Cholesterol; D002994:Clofibrate; D015248:Gemfibrozil; D008798:Mevalonic Acid