RRC ID 38246
著者 Sugatani J, Osabe M, Kurosawa M, Kitamura N, Ikari A, Miwa M.
タイトル Induction of UGT1A1 and CYP2B6 by an antimitogenic factor in HepG2 cells is mediated through suppression of cyclin-dependent kinase 2 activity: cell cycle-dependent expression.
ジャーナル Drug Metab Dispos
Abstract Hepatocyte growth factor (HGF), an antimitogenic factor for HepG2 cells, increased mRNA and protein levels of UGT1A1 and CYP2B6, as well as the endogenous cyclin-dependent kinase (CDK) inhibitors p16, p21, and p27 in HepG2 cells but not in HuH6, Caco2, or MCF7 cells. Treatment with 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126) (an extracellular signal-regulated kinase inhibitor) suppressed the HGF-induced expression of UGT1A1 and CYP2B6, as well as p16, p21, and p27 in HepG2 cells. The CDK inhibitor roscovitine also enhanced the expression of UGT1A1, CYP2B6, and CYP3A4. Transfection of anti-CDK2 siRNA led to elevated levels of UGT1A1, CYP2B6, and CYP3A4 in HepG2 and SW480 cells, whereas anti-CDK4 small interfering RNA (siRNA) did not significantly enhance the expression of these enzymes. In fact, CDK2 activity was decreased in HGF-treated HepG2 cells. In cells arrested in S phase by a thymidine block and then released into a synchronous cell cycle, there was a clear dissociation among the activation of CDK2 and the expression of UGT1A1, CYP2B6, and CYP3A4. Furthermore, the induction of CYP3A4 but not UGT1A1 or CYP2B6 mRNA expression by roscovitine was repressed in pregnane X receptor (PXR) siRNA-transfected HepG2 cells. Transfection with constitutive androstane receptor siRNA or PXR siRNA in HepG2 cells did not repress the HGF-stimulated expression of UGT1A1 mRNA. Taken together, our results show that the expression of UGT1A1 and CYP2B6 is negatively regulated through a CDK2 signaling pathway linked to cell cycle progression in HepG2 and SW480 cells, the mechanism of which may differ from that of CYP3A4 expression through PXR phosphorylated by CDK2.
巻・号 38(1)
ページ 177-86
公開日 2010-1-1
DOI 10.1124/dmd.109.029785
PII dmd.109.029785
PMID 19797611
MeSH Aryl Hydrocarbon Hydroxylases / genetics Aryl Hydrocarbon Hydroxylases / metabolism* Cell Cycle / drug effects Cell Cycle / physiology* Cell Line, Tumor Cell Proliferation / drug effects Cyclin-Dependent Kinase 2 / antagonists & inhibitors* Cyclin-Dependent Kinase 2 / genetics Cyclin-Dependent Kinase 2 / metabolism Cyclin-Dependent Kinase Inhibitor Proteins / genetics Cyclin-Dependent Kinase Inhibitor Proteins / metabolism Cyclin-Dependent Kinases / antagonists & inhibitors Cyclin-Dependent Kinases / genetics Cyclin-Dependent Kinases / metabolism Cytochrome P-450 CYP1A1 / genetics Cytochrome P-450 CYP1A1 / metabolism Cytochrome P-450 CYP2B6 Cytochrome P-450 CYP3A / genetics Cytochrome P-450 CYP3A / metabolism Enzyme Induction / drug effects Enzyme Induction / physiology Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors Extracellular Signal-Regulated MAP Kinases / metabolism Gene Expression / drug effects Gene Expression / genetics Gene Expression Regulation, Neoplastic / drug effects* Glucuronosyltransferase / genetics Glucuronosyltransferase / metabolism* Hep G2 Cells Hepatocyte Growth Factor / pharmacology* Histones / metabolism Humans Intercellular Signaling Peptides and Proteins / pharmacology JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors JNK Mitogen-Activated Protein Kinases / metabolism Oxidoreductases, N-Demethylating / genetics Oxidoreductases, N-Demethylating / metabolism* Phosphatidylinositol 3-Kinases / metabolism Phosphoinositide-3 Kinase Inhibitors Phosphorylation / drug effects Pregnane X Receptor Protein Kinase Inhibitors / pharmacology Purines / pharmacology RNA, Small Interfering / genetics Receptors, Cytoplasmic and Nuclear / genetics Receptors, Cytoplasmic and Nuclear / metabolism Receptors, Steroid / genetics Receptors, Steroid / metabolism Roscovitine Signal Transduction / drug effects Signal Transduction / physiology
IF 3.231
引用数 19
WOS 分野 PHARMACOLOGY & PHARMACY
リソース情報
ヒト・動物細胞 CACO-2(RCB0988)