title: Metabolism of thalidomide by human liver microsome cytochrome CYP2C19 is required for its antimyeloma and antiangiogenic activities in vitro.
abstract: In this study, we used a system of human liver microsomes to investigate the antimyeloma and antiangiogenic activities of thalidomide. Myeloma cells and human umbilical vein endothelial cells (HUVECs) were treated with thalidomide alone or thalidomide incubated with human liver microsomal protein. We found that thalidomide alone had no direct effect on several multiple myeloma cell lines (U266, NCI-H929, RPMI 8226, LP-1, CZ-1) or on HUVECs in vitro. However, when incubated with human liver microsomal protein, thalidomide (100 µg/ml) caused a decrease of 34.9-46.7% in cell viability in myeloma cells and 12% in HUVECs. Cell cycle analysis and apoptosis detection indicated that the decreases in cell viability were correlated with the induction of apoptosis. Thalidomide incubated with microsomal protein also influenced HUVEC migration and tube formation. These effects were partially reversed by omeprazole (10 µmol/l), a potent inhibitor of CYP2C19, suggesting that CYP2C19 is required for thalidomide to exhibit its antimyeloma and antiangiogenic activities.
authors.affiliation: Department of Hematology, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, China.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Li
authors.forename: Zujun
authors.initials: Z
authors.lastname: Jiang
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiao
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
mesh_terms: D020533:Angiogenesis Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D065731:Cytochrome P-450 CYP2C19; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D013792:Thalidomide / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; D013792:Thalidomide; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19