RRC ID 63638
著者 Yamazaki T, Tokiwa T.
タイトル Elevated levels of expression of cytochrome P450 3A4 in a human liver epithelial cell line in differentiation-inducing conditions.
ジャーナル Hum Cell
Abstract Cytochrome P450 (CYP) enzymes, especially CYP3A4 play a major role in the metabolism of xenobiotics in human liver. CYP3A4-expressing human liver or hepatoma cell lines may be good cell substitutes of human hepatocytes for drug metabolism studies. However, there are only a few cell lines expressing high levels of CYP3A4. The aim of this study is to investigate the expression of CYP3A4 and its mechanism in an immortalized non-tumorigenic human liver epithelial cell line, THLE-5b in differentiation-inducing conditions. When THLE-5b cells were cultivated in culture medium supplemented with hepatocytic differentiation-inducing factors, they showed hepatocytic morphology. In addition, elevated levels of expression not only of α1-antitrypsin (AAT) and albumin (ALB) mRNAs, but also of CYP3A4 mRNA, which are functional hepatocyte markers, were observed compared with the control. Among hepatocytic differentiation-inducing factors, dexamethasone (DEX) and insulin-transferrin-sodium selenite (ITS) seemed to be involved in elevation of expression of CYP3A4 mRNA. The mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor U0126 or the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 reduced CYP3A4 mRNA levels of THLE-5b cells. Furthermore, the CpG site of the CYP3A4 promoter region in THLE-5b cells was found to be unmethylated, although in low CYP3A4-expressing HepG2 cells, the site was methylated. In conclusion, THLE-5b cells, which are unmethylated at the CpG site of the CYP3A4 promoter region, express CYP3A4 mRNA through the MEK/ERK1/2 and PI3K/Akt signaling pathways and acquire hepatocytic functions in differentiation-inducing conditions. Thus, THLE-5b cells could be a useful cell system for the study of drug metabolism.
巻・号 34(3)
ページ 750-758
公開日 2021-5-1
DOI 10.1007/s13577-021-00487-2
PII 10.1007/s13577-021-00487-2
PMID 33495943
MeSH Cell Differentiation / genetics* Cell Line Cytochrome P-450 CYP3A / genetics* Cytochrome P-450 CYP3A / metabolism* Epithelial Cells / metabolism* Epithelial Cells / physiology* Gene Expression* Humans Liver / cytology* Liver / metabolism* MAP Kinase Signaling System Mitogen-Activated Protein Kinase Kinases / metabolism Phosphatidylinositol 3-Kinases / metabolism Signal Transduction Up-Regulation / genetics*
IF 3.463
リソース情報
ヒト・動物細胞 Hep G2(RCB1886)