2004年7月
c-Jun N-terminal kinase modulates 1,25-dihydroxyvitamin D-3-induced cytochrome P450 3A4 gene expression
DRUG METABOLISM AND DISPOSITION
- ,
- ,
- ,
- ,
- 巻
- 32
- 号
- 7
- 開始ページ
- 685
- 終了ページ
- 688
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1124/dmd.32.7.685
- 出版者・発行元
- AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
1,25-Dihydroxyvitamin D-3 (1,25(OH)(2)D-3) is known to induce the expression of cytochrome P450 3A4 (CYP3A4) in human colon carcinoma Caco-2 cells. Recently, it was demonstrated that the vitamin D receptor (VDR) regulates 1,25(OH)(2)D-3- induced CYP3A4 gene expression through the xenobiotic-responsive element and the vitamin D-responsive element located on the 5'-flanking region of the CYP3A4 gene. On the other hand, we previously reported that protein kinases such as protein kinase C and tyrosine kinases contribute to the induction of CYP3A4 mRNA by 1,25(OH)(2)D-3. In the present study, we examined the involvement of mitogen-activated protein kinases (MAPKs) in the 1,25(OH)(2)D-3-induced CYP3A4 gene expression using MAPK inhibitors. Curcumin, a c-Jun N-terminal kinase (JNK) pathway inhibitor, and anthra[1,9-cd]pyrazole-6(2H)-one (SP600125), a JNK inhibitor, suppressed the induction of CYP3A4 mRNA by 1,25(OH)(2)D-3, but not 2'-amino-3'-methoxyflavone (PD098059), a mitogen-activated protein kinase kinase-extracellular signal-regulated kinase (ERK) pathway inhibitor, or 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), a p38 inhibitor. In addition, we demonstrated that SP600125 dose-dependently inhibited the CYP3A4 promoter activity induced by 1,25(OH)(2)D-3 using the reporter plasmid of the CYP3A4 promoter. However, SP600125 did not affect 1,25(OH)(2)D-3-induced transactivation of the DR3 via VDR. These results indicate that JNK, but not ERK or p38, is required for the optimal activation of the CYP3A4 gene induced by 1,25(OH)(2)D-3.
- リンク情報
- ID情報
-
- DOI : 10.1124/dmd.32.7.685
- ISSN : 0090-9556
- PubMed ID : 15205382
- Web of Science ID : WOS:000222093500002